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package Sanger::CGP::Vagrent::Annotators::AbstractAnnotator; |
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##########LICENCE########## |
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# Copyright (c) 2014 Genome Research Ltd. |
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# |
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# Author: Cancer Genome Project cgpit@sanger.ac.uk |
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# |
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# This file is part of VAGrENT. |
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# |
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# VAGrENT is free software: you can redistribute it and/or modify it under |
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# the terms of the GNU Affero General Public License as published by the Free |
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# Software Foundation; either version 3 of the License, or (at your option) any |
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# later version. |
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# |
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# This program is distributed in the hope that it will be useful, but WITHOUT |
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# ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS |
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# FOR A PARTICULAR PURPOSE. See the GNU Affero General Public License for more |
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# details. |
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# |
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# You should have received a copy of the GNU Affero General Public License |
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# along with this program. If not, see <http://www.gnu.org/licenses/>. |
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##########LICENCE########## |
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use strict; |
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use Log::Log4perl; |
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use POSIX qw(ceil); |
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use Data::Dumper; |
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use Attribute::Abstract; |
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use Const::Fast qw(const); |
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use Sanger::CGP::Vagrent qw($VERSION); |
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use Sanger::CGP::Vagrent::Data::Annotation; |
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use Sanger::CGP::Vagrent::Data::AnnotationGroup; |
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use base qw(Sanger::CGP::Vagrent::Ontology::SequenceOntologyClassifier); |
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my $log = Log::Log4perl->get_logger(__PACKAGE__); |
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# constant reference values for consensus splice site values. |
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const my @CONSENSUS_SPLICE_OFFSETS => (-2, -1, 1, 2, 5); |
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const my $CONSENSUS_SPLICE_BEFORE_BOUNDRY => -2; |
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const my $CONSENSUS_SPLICE_AFTER_BOUNDRY => 5; |
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# constant value representing the cutoff for intronic calls |
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const my $INTRONIC_OFFSET_CUTOFF => 11; |
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const my $UPDOWNSTREAM_5KB_CUTOFF => 5000; |
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const my $UPSTREAM_2KB_CUTOFF => -2000; |
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const my $DOWNSTREAM_500BP_CUTOFF => 500; |
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1; |
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sub new { |
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my $proto = shift; |
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my $class = ref($proto) || $proto; |
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my $self = {}; |
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bless($self, $class); |
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$self->_init(@_); |
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$self->_ontologyInit(@_); |
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return $self; |
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} |
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sub getConsensusSpliceOffsets { |
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return @CONSENSUS_SPLICE_OFFSETS; |
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} |
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sub getAnnotation { |
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my ($self,$var) = @_; |
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my @ann = $self->_getAnnotation($var); |
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$self->_assignBookmarks(@ann); |
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if(exists $self->{'_only_bookmarked'} && $self->{'_only_bookmarked'}){ |
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my @out; |
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foreach my $a(@ann){ |
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if($a->hasBookmark()){ |
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push(@out,$a); |
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} |
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} |
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return @out; |
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} |
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return @ann; |
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} |
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sub _getAnnotation: Abstract; |
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sub addMessage { |
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my ($self,$msg) = @_; |
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push(@{$self->{_msg}},ref($self).": ".$msg); |
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} |
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sub _debug { |
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my $self = shift; |
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if(exists($self->{_debug}) && defined($self->{_debug}) && $self->{_debug}){ |
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return 1; |
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} else { |
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return 0; |
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} |
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} |
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sub getMessages { |
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my $self = shift; |
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return @{$self->{_msg}} if defined($self->{_msg}); |
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return undef; |
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} |
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sub _clearMessages { |
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shift->{_msg} = undef; |
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} |
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sub _assignBookmarks { |
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my ($self,@groups) = @_; |
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if(exists $self->{'_bookmarkers'} && defined $self->{'_bookmarkers'}){ |
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foreach my $bm (@{$self->{'_bookmarkers'}}){ |
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$bm->markAnnotation(@groups); |
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} |
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} |
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} |
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sub _isStartGained: Abstract; |
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sub _init { |
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my $self = shift; |
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my %vars = @_; |
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foreach my $k(keys(%vars)){ |
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if($k eq 'transcriptSource' && $vars{'transcriptSource'}->isa('Sanger::CGP::Vagrent::TranscriptSource::AbstractTranscriptSource')){ |
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$self->{'_transcriptSource'} = $vars{'transcriptSource'}; |
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} elsif($k eq 'bookmarker'){ |
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if(ref($vars{'bookmarker'}) eq 'ARRAY'){ |
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foreach my $tmp(@{$vars{'bookmarker'}}){ |
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if($tmp->isa('Sanger::CGP::Vagrent::Bookmarkers::AbstractBookmarker')){ |
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push(@{$self->{'_bookmarkers'}},$tmp); |
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} |
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} |
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} elsif($vars{'bookmarker'}->isa('Sanger::CGP::Vagrent::Bookmarkers::AbstractBookmarker')){ |
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push(@{$self->{'_bookmarkers'}},$vars{'bookmarker'}); |
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} |
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} elsif($k eq 'only_bookmarked'){ |
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$self->{'_only_bookmarked'} = $vars{'only_bookmarked'}; |
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} elsif($k eq 'debug' && $vars{'debug'}){ |
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$self->{'_debug'} = 1; |
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} |
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} |
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} |
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sub _getmRNAPositions { |
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my ($self,$mut,$tran) = @_; |
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my $exonBeforeInTrans = undef; |
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my $exonContainingStartInTrans = undef; |
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my $exonsDuringInTrans = undef; |
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my $exonContainingEndInTrans = undef; |
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my $exonAfterInTrans = undef; |
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foreach my $e ($tran->getExons){ |
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if($e->getChr() ne $mut->getChr()){ |
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# thats not right, chromosomes don't match; |
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my $msg = 'Unable to process this variant, chromosome doesnt match transcript'; |
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$self->addMessage($msg); |
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$log->error($msg); |
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return undef; |
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} |
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if($e->getMaxPos < $mut->getMinPos){ |
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# exon before mutation on genome, they don't overlap |
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if($tran->getStrand == 1){ |
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# we are the easy way up |
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$exonBeforeInTrans = $e; |
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} else { |
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# we are the tricky way up |
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unless(defined($exonAfterInTrans)){ |
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$exonAfterInTrans = $e; |
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} |
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} |
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next; |
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} |
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if($mut->getMinPos <= $e->getMinPos && $e->getMaxPos <= $mut->getMaxPos){ |
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# exon is completely covered by the mutation |
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push(@$exonsDuringInTrans,$e); |
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next; |
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} |
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if($mut->getMaxPos < $e->getMinPos){ |
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# exon after mutation on genome, they don't overlap |
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if($tran->getStrand == 1){ |
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# we are the easy way up |
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unless(defined($exonAfterInTrans)){ |
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$exonAfterInTrans = $e; |
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} |
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} else { |
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# we are the tricky way up |
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$exonBeforeInTrans = $e; |
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} |
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next; |
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} |
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if($e->getMinPos <= $mut->getMinPos && $mut->getMinPos <= $e->getMaxPos ){ |
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# start of mutation is in this exon on the genome |
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if($tran->getStrand == 1){ |
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# we are the easy way up |
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$exonContainingStartInTrans = $e; |
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} else { |
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# we are the tricky way up |
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$exonContainingEndInTrans = $e; |
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} |
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} |
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100
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if($e->getMinPos <= $mut->getMaxPos && $mut->getMaxPos <= $e->getMaxPos){ |
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# end of mutation is in this exon on the genome |
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100
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if($tran->getStrand == 1){ |
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# we are the easy way up |
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$exonContainingEndInTrans = $e; |
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} else { |
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# we are the tricky way up |
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$exonContainingStartInTrans = $e; |
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} |
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} |
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} |
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216
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if($self->_debug){ |
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print 'VAR '.Dumper($mut); |
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print 'BEFORE '.Dumper($exonBeforeInTrans); |
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print 'START '.Dumper($exonContainingStartInTrans); |
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print 'DURING '.Dumper($exonsDuringInTrans); |
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print 'END '.Dumper($exonContainingEndInTrans); |
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print 'AFTER '.Dumper($exonAfterInTrans); |
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} |
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my $mutTranStart = undef; |
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my $mutStartOffset = undef; |
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my $mutTranEnd = undef; |
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my $mutEndOffset = undef; |
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100
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if(!defined($exonBeforeInTrans) && |
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!defined($exonContainingStartInTrans)){ |
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# variant starts before the transcript, set start to special case 0 |
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my $tmpAfter; |
234
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if(defined($exonsDuringInTrans) && defined($exonsDuringInTrans->[0])){ |
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$tmpAfter = $exonsDuringInTrans->[0]; |
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} elsif(defined($exonContainingEndInTrans)){ |
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$tmpAfter = $exonContainingEndInTrans; |
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} else { |
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$tmpAfter = $exonAfterInTrans; |
240
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} |
241
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$mutTranStart = 0; |
242
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100
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if($tran->getStrand == 1){ |
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$mutStartOffset = $mut->getMinPos - $tmpAfter->getMinPos; |
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} else { |
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$mutStartOffset = $tmpAfter->getMaxPos - $mut->getMaxPos; |
246
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} |
247
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} elsif (defined($exonBeforeInTrans) && |
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!defined($exonContainingStartInTrans) && |
249
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!defined($exonsDuringInTrans) && |
250
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!defined($exonContainingEndInTrans) && |
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!defined($exonAfterInTrans)) { |
252
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# variant starts after the transcript, set start to special case 0 |
253
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$mutTranStart = 0; |
254
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100
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if($tran->getStrand == 1){ |
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$mutStartOffset = $mut->getMinPos - $exonBeforeInTrans->getMaxPos; |
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} else { |
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$mutStartOffset = $exonBeforeInTrans->getMinPos - $mut->getMaxPos; |
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} |
259
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} elsif(defined($exonContainingStartInTrans)){ |
260
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# mutations starts within an exon; |
261
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100
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if($tran->getStrand == 1){ |
262
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# we are the easy way up |
263
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$mutTranStart = ($mut->getMinPos - $exonContainingStartInTrans->getMinPos) + $exonContainingStartInTrans->getRnaMinPos; |
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$mutStartOffset = 0; |
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} else { |
266
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# we are the tricky way up |
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$mutTranStart = ($exonContainingStartInTrans->getMaxPos - $mut->getMaxPos) + $exonContainingStartInTrans->getRnaMinPos; |
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$mutStartOffset = 0; |
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} |
270
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print "START - $mutTranStart - $mutStartOffset\n" if($self->_debug); |
271
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} elsif(defined($exonBeforeInTrans)) { |
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# mutation starts between exons, this makes things harder |
273
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my $before = $exonBeforeInTrans; |
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my $after = undef; |
275
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my $beforeBoundry = undef; |
276
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my $afterBoundry = undef; |
277
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100
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if(defined($exonsDuringInTrans)){ |
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100
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278
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$after = $exonsDuringInTrans->[0]; |
279
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} elsif(defined($exonContainingEndInTrans)){ |
280
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$after = $exonContainingEndInTrans; |
281
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} else { |
282
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$after = $exonAfterInTrans; |
283
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} |
284
|
100
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if($tran->getStrand == 1){ |
285
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$beforeBoundry->{mut} = $mut->getMinPos; |
286
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$beforeBoundry->{exon} = $before->getMaxPos; |
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$beforeBoundry->{off} = $mut->getMinPos - $before->getMaxPos; |
288
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$beforeBoundry->{pos} = $before->getRnaMaxPos; |
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$afterBoundry->{mut} = $mut->getMinPos; |
290
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$afterBoundry->{exon} = $after->getMinPos; |
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|
|
$afterBoundry->{off} = $mut->getMinPos - $after->getMinPos; |
292
|
|
|
|
$afterBoundry->{pos} = $after->getRnaMinPos; |
293
|
|
|
|
} else { |
294
|
|
|
|
$beforeBoundry->{mut} = $mut->getMaxPos; |
295
|
|
|
|
$beforeBoundry->{exon} = $before->getMinPos; |
296
|
|
|
|
$beforeBoundry->{off} = $before->getMinPos - $mut->getMaxPos; |
297
|
|
|
|
$beforeBoundry->{pos} = $before->getRnaMaxPos; |
298
|
|
|
|
$afterBoundry->{mut} = $mut->getMaxPos; |
299
|
|
|
|
$afterBoundry->{exon} = $after->getMaxPos; |
300
|
|
|
|
$afterBoundry->{off} = $after->getMaxPos - $mut->getMaxPos; |
301
|
|
|
|
$afterBoundry->{pos} = $after->getRnaMinPos; |
302
|
|
|
|
} |
303
|
50
|
|
|
if($self->_debug){ |
304
|
|
|
|
print 'START BEFORE BOUNDRY '. Dumper($beforeBoundry); |
305
|
|
|
|
print 'START AFTER BOUNDRY '.Dumper($afterBoundry); |
306
|
|
|
|
} |
307
|
100
|
|
|
if($mut->isa('Sanger::CGP::Vagrent::Data::Insertion') && $beforeBoundry->{off} + $afterBoundry->{off} == 0 && $beforeBoundry->{pos} + 1 == $afterBoundry->{pos}){ |
308
|
|
|
|
# very special case. we have an insertion starting at the mid point of an odd length intron. To avoid confusion |
309
|
|
|
|
# we'll attach the start of the insertion to the exon after the insertion as that is going to be closer to the insertion end point |
310
|
|
|
|
$mutTranStart = $afterBoundry->{pos}; |
311
|
|
|
|
$mutStartOffset = $afterBoundry->{off}; |
312
|
|
|
|
} else { |
313
|
100
|
|
|
if(abs($beforeBoundry->{off}) > abs($afterBoundry->{off})){ |
314
|
|
|
|
$mutTranStart = $afterBoundry->{pos}; |
315
|
|
|
|
$mutStartOffset = $afterBoundry->{off}; |
316
|
|
|
|
} else { |
317
|
|
|
|
$mutTranStart = $beforeBoundry->{pos}; |
318
|
|
|
|
$mutStartOffset = $beforeBoundry->{off}; |
319
|
|
|
|
} |
320
|
|
|
|
} |
321
|
|
|
|
} else { |
322
|
|
|
|
my $msg = 'Unable to process this variant, very strange coordinate data'; |
323
|
|
|
|
$self->addMessage($msg); |
324
|
|
|
|
$log->error($msg); |
325
|
|
|
|
return undef; |
326
|
|
|
|
} |
327
|
100
|
|
|
if(!defined($exonBeforeInTrans) && |
|
100
|
|
|
|
|
100
|
|
|
|
|
50
|
|
|
|
328
|
|
|
|
!defined($exonContainingStartInTrans) && |
329
|
|
|
|
!defined($exonsDuringInTrans) && |
330
|
|
|
|
!defined($exonContainingEndInTrans) && |
331
|
|
|
|
defined($exonAfterInTrans)){ |
332
|
|
|
|
# variant ends before the transcripts starts, set end to special case 0 |
333
|
|
|
|
$mutTranEnd = 0; |
334
|
100
|
|
|
if($tran->getStrand == 1){ |
335
|
|
|
|
$mutEndOffset = $mut->getMaxPos - $exonAfterInTrans->getMinPos; |
336
|
|
|
|
} else { |
337
|
|
|
|
$mutEndOffset = $exonAfterInTrans->getMaxPos - $mut->getMinPos; |
338
|
|
|
|
} |
339
|
|
|
|
} elsif(!defined($exonContainingEndInTrans) && |
340
|
|
|
|
!defined($exonAfterInTrans)){ |
341
|
|
|
|
# variant ends after the transcripts ends, set end to special case 0 |
342
|
|
|
|
my $tmpBefore; |
343
|
100
|
|
|
if(defined($exonsDuringInTrans) && defined($exonsDuringInTrans->[scalar(@$exonsDuringInTrans) - 1])){ |
|
100
|
|
|
|
344
|
|
|
|
$tmpBefore = $exonsDuringInTrans->[scalar(@$exonsDuringInTrans) - 1]; |
345
|
|
|
|
} elsif(defined($exonContainingStartInTrans)){ |
346
|
|
|
|
$tmpBefore = $exonContainingStartInTrans; |
347
|
|
|
|
} else { |
348
|
|
|
|
$tmpBefore = $exonBeforeInTrans; |
349
|
|
|
|
} |
350
|
|
|
|
$mutTranEnd = 0; |
351
|
100
|
|
|
if($tran->getStrand == 1){ |
352
|
|
|
|
$mutEndOffset = $mut->getMaxPos - $tmpBefore->getMaxPos; |
353
|
|
|
|
} else { |
354
|
|
|
|
$mutEndOffset = $tmpBefore->getMinPos - $mut->getMinPos; |
355
|
|
|
|
} |
356
|
|
|
|
} elsif(defined($exonContainingEndInTrans)){ |
357
|
|
|
|
# mutations ends within an exon; |
358
|
100
|
|
|
if($tran->getStrand == 1){ |
359
|
|
|
|
# we are the easy way up |
360
|
|
|
|
$mutTranEnd = ($mut->getMaxPos - $exonContainingEndInTrans->getMinPos) + $exonContainingEndInTrans->getRnaMinPos; |
361
|
|
|
|
$mutEndOffset = 0; |
362
|
|
|
|
} else { |
363
|
|
|
|
# we are the tricky way up |
364
|
|
|
|
$mutTranEnd = ($exonContainingEndInTrans->getMaxPos - $mut->getMinPos) + $exonContainingEndInTrans->getRnaMinPos; |
365
|
|
|
|
$mutEndOffset = 0; |
366
|
|
|
|
} |
367
|
50
|
|
|
print "END - $mutTranEnd - $mutEndOffset\n" if($self->_debug); |
368
|
|
|
|
} elsif(defined($exonAfterInTrans)) { |
369
|
|
|
|
# mutation ends between exons, this makes things harder |
370
|
|
|
|
my $before = undef; |
371
|
|
|
|
my $after = $exonAfterInTrans; |
372
|
|
|
|
my $beforeBoundry = undef; |
373
|
|
|
|
my $afterBoundry = undef; |
374
|
100
|
|
|
if(defined($exonsDuringInTrans)){ |
|
100
|
|
|
|
375
|
|
|
|
$before = $exonsDuringInTrans->[scalar(@$exonsDuringInTrans) - 1]; |
376
|
|
|
|
} elsif(defined($exonContainingStartInTrans)){ |
377
|
|
|
|
$before = $exonContainingStartInTrans; |
378
|
|
|
|
} else { |
379
|
|
|
|
$before = $exonBeforeInTrans; |
380
|
|
|
|
} |
381
|
100
|
|
|
if($tran->getStrand == 1){ |
382
|
|
|
|
$beforeBoundry->{mut} = $mut->getMaxPos; |
383
|
|
|
|
$beforeBoundry->{exon} = $before->getMaxPos; |
384
|
|
|
|
$beforeBoundry->{off} = $mut->getMaxPos - $before->getMaxPos; |
385
|
|
|
|
$beforeBoundry->{pos} = $before->getRnaMaxPos; |
386
|
|
|
|
$afterBoundry->{mut} = $mut->getMaxPos; |
387
|
|
|
|
$afterBoundry->{exon} = $after->getMinPos; |
388
|
|
|
|
$afterBoundry->{off} = $mut->getMaxPos - $after->getMinPos; |
389
|
|
|
|
$afterBoundry->{pos} = $after->getRnaMinPos; |
390
|
|
|
|
} else { |
391
|
|
|
|
$beforeBoundry->{mut} = $mut->getMinPos; |
392
|
|
|
|
$beforeBoundry->{exon} = $before->getMinPos; |
393
|
|
|
|
$beforeBoundry->{off} = $before->getMinPos - $mut->getMinPos; |
394
|
|
|
|
$beforeBoundry->{pos} = $before->getRnaMaxPos; |
395
|
|
|
|
$afterBoundry->{mut} = $mut->getMinPos; |
396
|
|
|
|
$afterBoundry->{exon} = $after->getMaxPos; |
397
|
|
|
|
$afterBoundry->{off} = $after->getMaxPos - $mut->getMinPos; |
398
|
|
|
|
$afterBoundry->{pos} = $after->getRnaMinPos; |
399
|
|
|
|
} |
400
|
50
|
|
|
if($self->_debug){ |
401
|
|
|
|
print 'END BEFORE BOUNDRY '. Dumper($beforeBoundry); |
402
|
|
|
|
print 'END AFTER BOUNDRY '.Dumper($afterBoundry); |
403
|
|
|
|
} |
404
|
100
|
|
|
if($mut->isa('Sanger::CGP::Vagrent::Data::Insertion') && $beforeBoundry->{off} + $afterBoundry->{off} == 1 && $beforeBoundry->{pos} + 1 == $afterBoundry->{pos}){ |
405
|
|
|
|
# very special case. we have an insertion dead centre of an evenly sized intron. To avoid confusion |
406
|
|
|
|
# we'll attach the end of the insertion to the exon before the insertion as that is the same as the start |
407
|
|
|
|
$mutTranEnd = $beforeBoundry->{pos}; |
408
|
|
|
|
$mutEndOffset = $beforeBoundry->{off}; |
409
|
|
|
|
} else { |
410
|
100
|
|
|
if(abs($beforeBoundry->{off}) > abs($afterBoundry->{off})){ |
411
|
|
|
|
$mutTranEnd = $afterBoundry->{pos}; |
412
|
|
|
|
$mutEndOffset = $afterBoundry->{off}; |
413
|
|
|
|
} else { |
414
|
|
|
|
$mutTranEnd = $beforeBoundry->{pos}; |
415
|
|
|
|
$mutEndOffset = $beforeBoundry->{off}; |
416
|
|
|
|
} |
417
|
|
|
|
} |
418
|
|
|
|
} else { |
419
|
|
|
|
my $msg = 'Unable to process this variant, very strange coordinate data'; |
420
|
|
|
|
$self->addMessage($msg); |
421
|
|
|
|
$log->error($msg); |
422
|
|
|
|
return undef; |
423
|
|
|
|
} |
424
|
50
|
|
|
print "mRNA VAR START = $mutTranStart $mutStartOffset\nmRNA VAR END = $mutTranEnd $mutEndOffset\n" if($self->_debug); |
425
|
|
|
|
return ($mutTranStart,$mutStartOffset,$mutTranEnd,$mutEndOffset); |
426
|
|
|
|
} |
427
|
|
|
|
|
428
|
|
|
|
sub _buildProteinAnnotation { |
429
|
|
441
|
|
my ($self,$var,$tran,$cAnnot,$rAnnot) = @_; |
430
|
|
|
|
my @classes; |
431
|
|
|
|
my $wtDna = $tran->getCdsSeq; |
432
|
|
|
|
my ($prePad,$postPad) = $self->_calculateCdsTranslationPadStrings($tran); |
433
|
|
|
|
my $wtProt = Bio::Seq->new(-seq => $prePad . $wtDna . $postPad)->translate->seq(); # wild type protein sequence |
434
|
100
|
|
|
unless($self->_canAnnotateToProtein($tran,$cAnnot)){ |
435
|
100
|
|
|
if($cAnnot->hasClassification($self->getComplexChangeVariantClass) && $cAnnot->getDescription eq 'c.0'){ |
436
|
|
|
|
# special case, the CDS has completely gone so the protein must follow. |
437
|
|
|
|
return $self->_buildRemovedProteinAnnotation($var,$tran,$wtProt,($self->getDeletionClass)); |
438
|
|
|
|
} |
439
|
|
|
|
my $msg = 'CDS annotation is non-coding or too complex, cant annotate this'; |
440
|
|
|
|
$self->addMessage($msg); |
441
|
|
|
|
$log->info($msg); |
442
|
|
|
|
my $pAnnot = $self->_buildUnknownProteinAnnotation($var,$tran,$cAnnot,length($wtProt),@classes); |
443
|
|
|
|
my $coversStart = 0; |
444
|
|
|
|
my $coversEnd = 0; |
445
|
|
|
|
|
446
|
100
|
|
|
$coversStart = 1 if($self->_coversStartCodon($tran,$cAnnot)); |
447
|
100
|
|
|
$coversEnd = 1 if($self->_coversStopCodon($tran,$cAnnot)); |
448
|
100
|
|
|
if($coversStart){ |
449
|
|
|
|
$pAnnot->addClassification($self->getStartLostVariantClass); |
450
|
|
|
|
} |
451
|
100
|
|
|
if($coversEnd){ |
452
|
|
|
|
$pAnnot->addClassification($self->getStopLostVariantClass); |
453
|
|
|
|
} |
454
|
|
|
|
return $pAnnot; |
455
|
|
|
|
} |
456
|
|
|
|
my $cdsMinPos = $self->_getCdsMinPosForProteinCalculation($cAnnot); |
457
|
|
|
|
my $cdsMaxPos = $self->_getCdsMaxPosForProteinCalculation($cAnnot); |
458
|
|
|
|
my $desc = undef; |
459
|
|
|
|
my $mutProtMin = undef; |
460
|
|
|
|
my $mutProtMax = undef; |
461
|
|
|
|
my $wt = undef; |
462
|
|
|
|
my $mt = undef; |
463
|
|
|
|
my $subtype = undef; |
464
|
|
|
|
my $type = undef; |
465
|
50
|
|
|
unless(defined $cdsMinPos && defined $cdsMaxPos) { |
466
|
|
|
|
# something has gone wrong |
467
|
|
|
|
return undef; |
468
|
|
|
|
} |
469
|
|
|
|
|
470
|
|
|
|
my $mtDna = $self->_getMutatedCdsSequence($wtDna,$cdsMinPos,$cdsMaxPos,$cAnnot->getMt()); |
471
|
|
|
|
my $mtProt = Bio::Seq->new(-seq => $prePad . $mtDna . $postPad)->translate->seq(); # mutant protein sequence |
472
|
|
|
|
my $maxMtProt = Bio::Seq->new(-seq => $prePad . $mtDna . substr($tran->getcDNASeq,$tran->getCdsMaxPos()))->translate->seq(); # maximised protein sequence, overruns the natural stop and translates to the end of the transcript |
473
|
100
|
|
|
if($wtProt eq $mtProt){ |
|
100
|
|
|
|
474
|
|
|
|
# wt and mt protein sequences are the same, its silent |
475
|
|
|
|
$mutProtMin = ceil(($cAnnot->getMinPos / 3)); |
476
|
|
|
|
$mutProtMax = ceil(($cAnnot->getMaxPos / 3)); |
477
|
|
|
|
$wt = substr($wtProt,($mutProtMin - 1),(($mutProtMax - $mutProtMin) + 1)); |
478
|
|
|
|
$mt = substr($mtProt,($mutProtMin - 1),(($mutProtMax - $mutProtMin) + 1)); |
479
|
50
|
|
|
if(length($wt) == 1 && length($mt) == 1 && $mutProtMin == $mutProtMax){ |
480
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.$mt; |
481
|
|
|
|
} else { |
482
|
|
|
|
$desc = 'p.(=)'; |
483
|
|
|
|
} |
484
|
|
|
|
$type = $self->_getDefaultProteinAnnotationType(); |
485
|
|
|
|
$subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
486
|
50
|
|
|
if($wt eq '*'){ |
487
|
|
|
|
push(@classes,$self->getStopRetainedVariantClass); |
488
|
|
|
|
} else { |
489
|
|
|
|
push(@classes,$self->getSynonymousVariantClass); |
490
|
|
|
|
} |
491
|
|
|
|
} elsif($cAnnot->hasClassification($self->getFrameShiftVariantClass)){ |
492
|
|
|
|
# frame shift |
493
|
50
|
|
|
if($wtProt eq $maxMtProt || $self->_sequenceStartsWithSequence($maxMtProt,$wtProt)){ |
494
|
|
|
|
my $msg = 'very strange frameshift, there is no change in the protein sequence so calling it unknown'; |
495
|
|
|
|
$self->addMessage($msg); |
496
|
|
|
|
$log->info($msg); |
497
|
|
|
|
return $self->_buildUnknownProteinAnnotation($var,$tran,$cAnnot,length($wtProt),@classes); |
498
|
|
|
|
} |
499
|
|
|
|
($subtype,$wt,$mt,$mutProtMin,$mutProtMax,$desc) = $self->_calculateFrameShiftProteinChange($wtProt,$maxMtProt); |
500
|
100
|
|
|
if($mutProtMin == 1){ |
501
|
|
|
|
# its frame shifted the start codon, no idea what this is going to cause. |
502
|
|
|
|
push(@classes,$self->getStartLostVariantClass); |
503
|
|
|
|
return $self->_buildUnknownProteinAnnotation($var,$tran,$cAnnot,length($wtProt),@classes); |
504
|
|
|
|
} |
505
|
|
|
|
$type = Sanger::CGP::Vagrent::Data::Annotation::getFrameShiftAnnotationType(); |
506
|
|
|
|
push(@classes,$self->getFrameShiftVariantClass); |
507
|
|
|
|
} else { |
508
|
|
|
|
$wt = $wtProt; |
509
|
|
|
|
$mt = $mtProt; |
510
|
|
|
|
$mutProtMin = 0; |
511
|
|
|
|
while(substr($wt,0,1) eq substr($mt,0,1)){ |
512
|
|
|
|
substr($wt,0,1,''); |
513
|
|
|
|
substr($mt,0,1,''); |
514
|
|
|
|
$mutProtMin++; |
515
|
|
|
|
} |
516
|
|
|
|
while(substr($wt,-1,1) eq substr($mt,-1,1)){ |
517
|
|
|
|
substr($wt,-1,1,''); |
518
|
|
|
|
substr($mt,-1,1,''); |
519
|
|
|
|
} |
520
|
|
|
|
|
521
|
|
|
|
#warn "|$wt| to |$mt|\n"; |
522
|
100
|
|
|
if($wt ne ''){ |
|
50
|
|
|
|
523
|
|
|
|
# wild type residue has been changed |
524
|
100
|
|
|
if($mt ne '' && length($wt) == length($mt) && length($wt) == 1){ |
|
100
|
|
|
|
|
50
|
|
|
|
525
|
|
|
|
# its a simple sub |
526
|
|
|
|
$mutProtMin++; |
527
|
|
|
|
$mutProtMax = $mutProtMin; |
528
|
|
|
|
$type = Sanger::CGP::Vagrent::Data::Annotation::getSubstitutionAnnotationType(); |
529
|
|
|
|
$subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
530
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.$mt; |
531
|
|
|
|
push(@classes,$self->getSubstitutionClass); |
532
|
50
|
|
|
if($wt eq $mt){ |
533
|
|
|
|
# this could still happen, but it should have already been caught |
534
|
|
|
|
$desc = 'p.(=)'; |
535
|
0
|
|
|
if($wt eq '*'){ |
536
|
|
|
|
push(@classes,$self->getStopRetainedVariantClass); |
537
|
|
|
|
} else { |
538
|
|
|
|
push(@classes,$self->getSynonymousVariantClass); |
539
|
|
|
|
} |
540
|
|
|
|
} else { |
541
|
100
|
|
|
if($mt eq '*'){ |
|
100
|
|
|
|
|
100
|
|
|
|
542
|
|
|
|
push(@classes,$self->getStopGainedVariantClass); |
543
|
|
|
|
} elsif($wt eq '*'){ |
544
|
|
|
|
push(@classes,$self->getStopLostVariantClass); |
545
|
|
|
|
} elsif($wt eq 'M' && $mutProtMin == 1){ |
546
|
|
|
|
push(@classes,$self->getStartLostVariantClass); |
547
|
|
|
|
} else { |
548
|
|
|
|
push(@classes,$self->getNonSynonymousVariantClass); |
549
|
|
|
|
} |
550
|
|
|
|
} |
551
|
|
|
|
} elsif ($mt ne '' && (length($wt) > 1 || length($mt) > 1)){ |
552
|
|
|
|
# complex sub |
553
|
|
|
|
$mutProtMin++; |
554
|
|
|
|
$mutProtMax = ($mutProtMin + length($wt)) - 1; |
555
|
|
|
|
$type = Sanger::CGP::Vagrent::Data::Annotation::getComplexAnnotationType(); |
556
|
|
|
|
$subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
557
|
100
|
|
|
if($mt =~ s/^(.*?\*).*$/$1/ || $mt eq '*'){ |
558
|
|
|
|
# this variant introduces a stop codon |
559
|
|
|
|
push(@classes,$self->getStopGainedVariantClass); |
560
|
|
|
|
push(@classes,$self->getComplexIndelClass); |
561
|
|
|
|
} else { |
562
|
|
|
|
push(@classes,$self->getComplexIndelClass); |
563
|
|
|
|
} |
564
|
100
|
|
|
if($mutProtMin == $mutProtMax){ |
565
|
|
|
|
# replaces single WT residue |
566
|
|
|
|
$desc = 'p.'.substr($wtProt,($mutProtMin - 1),1).$mutProtMin.'delins'.$mt; |
567
|
|
|
|
} else { |
568
|
|
|
|
$desc = 'p.'.substr($wtProt,($mutProtMin - 1),1).$mutProtMin.'_'.substr($wtProt,($mutProtMax - 1),1).$mutProtMax.'delins'.$mt; |
569
|
|
|
|
} |
570
|
|
|
|
} elsif($mt eq ''){ |
571
|
|
|
|
# its an inframe deletion |
572
|
|
|
|
$mt = '-'; |
573
|
|
|
|
$mutProtMin++; |
574
|
|
|
|
$mutProtMax = ($mutProtMin + length($wt)) - 1; |
575
|
|
|
|
$type = Sanger::CGP::Vagrent::Data::Annotation::getDeletionAnnotationType(); |
576
|
|
|
|
$subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
577
|
50
|
|
|
if($mutProtMin == $mutProtMax){ |
578
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'del'.$wt; |
579
|
|
|
|
} else { |
580
|
|
|
|
$desc = 'p.'.substr($wt,0,1).$mutProtMin.'_'.substr($wt,-1,1).$mutProtMax.'del'.$wt; |
581
|
|
|
|
} |
582
|
|
|
|
push(@classes,$self->getInFrameCodonLossVariantClass); |
583
|
|
|
|
} |
584
|
|
|
|
} elsif($wt eq '' && $mt ne '' && length($mt) > 0){ |
585
|
|
|
|
# This is an in frame insertion |
586
|
|
|
|
$wt = '-'; |
587
|
|
|
|
$mutProtMax = $mutProtMin + 1; |
588
|
|
|
|
$type = Sanger::CGP::Vagrent::Data::Annotation::getInsertionAnnotationType(); |
589
|
|
|
|
$subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
590
|
100
|
|
|
if($mt =~ s/^(.*?\*).*$/$1/){ |
591
|
|
|
|
# this variant introduces a stop codon |
592
|
|
|
|
push(@classes,$self->getStopGainedVariantClass); |
593
|
50
|
|
|
if(length($mt) > 1){ |
594
|
|
|
|
push(@classes,$self->getInFrameCodonGainVariantClass); |
595
|
|
|
|
} |
596
|
|
|
|
} else { |
597
|
|
|
|
push(@classes,$self->getInFrameCodonGainVariantClass); |
598
|
|
|
|
} |
599
|
|
|
|
$desc = 'p.'.substr($wtProt,($mutProtMin - 1),1).$mutProtMin.'_'.substr($wtProt,($mutProtMax - 1),1).$mutProtMax.'ins'.$mt; |
600
|
|
|
|
} else { |
601
|
|
|
|
my $msg = 'Unhandled case, reporting unknown protein annotation'; |
602
|
|
|
|
$self->addMessage($msg); |
603
|
|
|
|
$log->info($msg); |
604
|
|
|
|
return $self->_buildUnknownProteinAnnotation($var,$tran,$cAnnot,length($wtProt),@classes); |
605
|
|
|
|
} |
606
|
|
|
|
} |
607
|
|
|
|
|
608
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new( wt => $wt, |
609
|
|
|
|
mt => $mt, |
610
|
|
|
|
minpos => $mutProtMin, |
611
|
|
|
|
minOffset => 0, |
612
|
|
|
|
maxpos => $mutProtMax, |
613
|
|
|
|
maxOffset => 0, |
614
|
|
|
|
acc => $tran->getProteinAccession, |
615
|
|
|
|
accversion => $tran->getProteinAccessionVersion, |
616
|
|
|
|
db => $tran->getDatabase, |
617
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
618
|
|
|
|
seqlength => length($wtProt), |
619
|
|
|
|
description => $desc, |
620
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getProteinAnnotationContext(), |
621
|
|
|
|
type => $type, |
622
|
|
|
|
subtype => $subtype); |
623
|
|
|
|
$anno->addClassification(@classes); |
624
|
|
|
|
return $anno; |
625
|
|
|
|
} |
626
|
|
|
|
|
627
|
|
4
|
|
sub _getMutatedCdsSequence: Abstract; |
628
|
|
|
|
|
629
|
|
4
|
|
sub _getCdsMinPosForProteinCalculation: Abstract; |
630
|
|
|
|
|
631
|
|
4
|
|
sub _getCdsMaxPosForProteinCalculation: Abstract; |
632
|
|
|
|
|
633
|
|
|
|
sub _buildCDSAnnotation { |
634
|
|
441
|
|
my ($self,$var,$tran,$rAnnot) = @_; |
635
|
|
|
|
my @classes; |
636
|
100
|
|
|
unless($self->_canAnnotateToCDS($tran,$rAnnot)){ |
637
|
|
|
|
my $msg = 'mRNA annotation doesnt affect the CDS, cant annotate this'; |
638
|
|
|
|
$self->addMessage($msg); |
639
|
|
|
|
$log->info($msg); |
640
|
|
|
|
return $self->_buildUnknownCDSAnnotation($var,$tran,$rAnnot,@classes); |
641
|
|
|
|
} |
642
|
|
|
|
my ($cdsMin,$cdsMinOffset,$cdsMax,$cdsMaxOffset) = (undef,undef,undef,undef); |
643
|
100
|
|
|
if($rAnnot->getMinPos < $tran->getCdsMinPos){ |
|
100
|
|
|
|
644
|
|
|
|
$cdsMin = 1; |
645
|
|
|
|
$cdsMinOffset = 0; |
646
|
|
|
|
} elsif($rAnnot->getMinPos == $tran->getCdsMinPos && $rAnnot->getMinOffset() < 0){ |
647
|
|
|
|
$cdsMin = 1; |
648
|
50
|
|
|
if($self->_isIntronicOffsetDistance($rAnnot->getMinOffset())){ |
649
|
|
|
|
$cdsMinOffset = 0; |
650
|
|
|
|
} else { |
651
|
|
|
|
$cdsMinOffset = $rAnnot->getMinOffset(); |
652
|
|
|
|
} |
653
|
|
|
|
} else { |
654
|
|
|
|
$cdsMin = ($rAnnot->getMinPos - $tran->getCdsMinPos) + 1; |
655
|
|
|
|
$cdsMinOffset = $rAnnot->getMinOffset(); |
656
|
|
|
|
} |
657
|
|
|
|
|
658
|
100
|
|
|
if($rAnnot->getMaxPos > $tran->getCdsMaxPos){ |
|
50
|
|
|
|
659
|
|
|
|
$cdsMax = length($tran->getCdsSeq); |
660
|
|
|
|
$cdsMaxOffset = 0; |
661
|
|
|
|
} elsif($rAnnot->getMaxPos == $tran->getCdsMaxPos && $rAnnot->getMaxOffset() > 0){ |
662
|
|
|
|
$cdsMax = length($tran->getCdsSeq); |
663
|
0
|
|
|
if($self->_isIntronicOffsetDistance($rAnnot->getMaxOffset())){ |
664
|
|
|
|
$cdsMaxOffset = 0; |
665
|
|
|
|
} else { |
666
|
|
|
|
$cdsMaxOffset = $rAnnot->getMaxOffset(); |
667
|
|
|
|
} |
668
|
|
|
|
} else { |
669
|
|
|
|
$cdsMax = ($rAnnot->getMaxPos() - $tran->getCdsMinPos) + 1; |
670
|
|
|
|
$cdsMaxOffset = $rAnnot->getMaxOffset(); |
671
|
|
|
|
} |
672
|
|
|
|
|
673
|
50
|
|
|
print "CDS: $cdsMin , $cdsMinOffset - $cdsMax, $cdsMaxOffset\n" if $self->_debug(); |
674
|
|
|
|
|
675
|
|
|
|
my $wt = $self->_getWildTypeStringForCDSAnno($var,$tran,$rAnnot); |
676
|
|
|
|
my $mt = $self->_getMutantStringForCDSAnno($var,$tran,$rAnnot); |
677
|
|
|
|
my $desc = $self->_getCDSDescriptionString($tran,$cdsMin,$cdsMax,$cdsMinOffset,$cdsMaxOffset,$wt,$mt); |
678
|
|
|
|
my $subtype = $rAnnot->getSubtype(); |
679
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new( wt => uc($wt), |
680
|
|
|
|
mt => uc($mt), |
681
|
|
|
|
minpos => $cdsMin, |
682
|
|
|
|
minOffset => $cdsMinOffset, |
683
|
|
|
|
maxpos => $cdsMax, |
684
|
|
|
|
maxOffset => $cdsMaxOffset, |
685
|
|
|
|
acc => $tran->getAccession, |
686
|
|
|
|
accversion => $tran->getAccessionVersion, |
687
|
|
|
|
db => $tran->getDatabase, |
688
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
689
|
|
|
|
seqlength => length($tran->getCdsSeq), |
690
|
|
|
|
description => $desc, |
691
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext(), |
692
|
|
|
|
type => $self->_getDefaultCDSAnnotationType(), |
693
|
|
|
|
subtype => $subtype); |
694
|
|
|
|
|
695
|
|
|
|
foreach my $rc($rAnnot->getClassifications){ |
696
|
100
|
|
|
next if($rc eq $self->get5KBUpStreamVariantClass || |
697
|
|
|
|
$rc eq $self->get2KBUpStreamVariantClass || |
698
|
|
|
|
$rc eq $self->get5KBDownStreamVariantClass || |
699
|
|
|
|
$rc eq $self->get500BPDownStreamVariantClass ); |
700
|
|
|
|
$anno->addClassification($rc); |
701
|
|
|
|
} |
702
|
|
|
|
$anno->addClassification(@classes); |
703
|
|
|
|
return $anno; |
704
|
|
|
|
|
705
|
|
|
|
|
706
|
|
|
|
|
707
|
|
|
|
} |
708
|
|
|
|
|
709
|
|
4
|
|
sub _getDefaultCDSAnnotationType: Abstract; |
710
|
|
|
|
|
711
|
|
4
|
|
sub _getDefaultProteinAnnotationType: Abstract; |
712
|
|
|
|
|
713
|
|
4
|
|
sub _getWildTypeStringForCDSAnno: Abstract; |
714
|
|
|
|
|
715
|
|
4
|
|
sub _getMutantStringForCDSAnno: Abstract; |
716
|
|
|
|
|
717
|
|
4
|
|
sub _getCDSDescriptionString: Abstract; |
718
|
|
|
|
|
719
|
|
|
|
sub _buildUnknownCDSAnnotation { |
720
|
|
152
|
|
my ($self,$mut,$tran,$rnaAnno,@classes) = @_; |
721
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new( wt => '?', |
722
|
|
|
|
mt => '?', |
723
|
|
|
|
minpos => 0, |
724
|
|
|
|
minOffset => 0, |
725
|
|
|
|
maxpos => 0, |
726
|
|
|
|
maxOffset => 0, |
727
|
|
|
|
acc => $tran->getAccession, |
728
|
|
|
|
accversion => $tran->getAccessionVersion, |
729
|
|
|
|
db => $tran->getDatabase, |
730
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
731
|
|
|
|
seqlength => length($tran->getCdsSeq), |
732
|
|
|
|
description => 'c.?', |
733
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext(), |
734
|
|
|
|
type => Sanger::CGP::Vagrent::Data::Annotation::getUnknownAnnotationType(), |
735
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getPositionOffSequenceSubtype()); |
736
|
|
|
|
$anno->addClassification(@classes); |
737
|
|
|
|
$anno->addClassification($self->getUnknownVariantClass); |
738
|
|
|
|
return $anno; |
739
|
|
|
|
} |
740
|
|
|
|
|
741
|
|
|
|
sub _buildUnaffectedCDSAnnotation { |
742
|
|
0
|
|
my ($self,$mut,$tran,$rnaAnno,@classes) = @_; |
743
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new(wt => '-', |
744
|
|
|
|
mt => '-', |
745
|
|
|
|
minpos => 0, |
746
|
|
|
|
minOffset => 0, |
747
|
|
|
|
maxpos => 0, |
748
|
|
|
|
maxOffset => 0, |
749
|
|
|
|
acc => $tran->getAccession, |
750
|
|
|
|
accversion => $tran->getAccessionVersion, |
751
|
|
|
|
db => $tran->getDatabase, |
752
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
753
|
|
|
|
seqlength => length($tran->getCdsSeq), |
754
|
|
|
|
description => 'c.=', |
755
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext(), |
756
|
|
|
|
type => Sanger::CGP::Vagrent::Data::Annotation::getUnknownAnnotationType(), |
757
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getNoneAnnotationSubtype()); |
758
|
|
|
|
$anno->addClassification(@classes); |
759
|
|
|
|
return $anno; |
760
|
|
|
|
} |
761
|
|
|
|
|
762
|
|
|
|
sub _buildUnknownProteinAnnotation { |
763
|
|
377
|
|
my ($self,$mut,$tran,$cdsAnno,$protLength,@classes) = @_; |
764
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new(wt => '?', |
765
|
|
|
|
mt => '?', |
766
|
|
|
|
minpos => 0, |
767
|
|
|
|
minOffset => 0, |
768
|
|
|
|
maxpos => 0, |
769
|
|
|
|
maxOffset => 0, |
770
|
|
|
|
acc => $tran->getProteinAccession, |
771
|
|
|
|
accversion => $tran->getProteinAccessionVersion, |
772
|
|
|
|
db => $tran->getDatabase, |
773
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
774
|
|
|
|
seqlength => $protLength, |
775
|
|
|
|
description => 'p.?', |
776
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getProteinAnnotationContext(), |
777
|
|
|
|
type => Sanger::CGP::Vagrent::Data::Annotation::getUnknownAnnotationType(), |
778
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getPositionOffSequenceSubtype()); |
779
|
|
|
|
$anno->addClassification(@classes); |
780
|
|
|
|
$anno->addClassification($self->getUnknownVariantClass); |
781
|
|
|
|
return $anno; |
782
|
|
|
|
} |
783
|
|
|
|
|
784
|
|
|
|
sub _buildUnaffectedProteinAnnotation { |
785
|
|
0
|
|
my ($self,$mut,$tran,$cdsAnno,$protLength,@classes) = @_; |
786
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new(wt => '-', |
787
|
|
|
|
mt => '-', |
788
|
|
|
|
minpos => 0, |
789
|
|
|
|
minOffset => 0, |
790
|
|
|
|
maxpos => 0, |
791
|
|
|
|
maxOffset => 0, |
792
|
|
|
|
acc => $tran->getProteinAccession, |
793
|
|
|
|
accversion => $tran->getProteinAccessionVersion, |
794
|
|
|
|
db => $tran->getDatabase, |
795
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
796
|
|
|
|
seqlength => $protLength, |
797
|
|
|
|
description => 'p.=', |
798
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getProteinAnnotationContext(), |
799
|
|
|
|
type => Sanger::CGP::Vagrent::Data::Annotation::getUnknownAnnotationType(), |
800
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getNoneAnnotationSubtype()); |
801
|
|
|
|
$anno->addClassification(@classes); |
802
|
|
|
|
return $anno; |
803
|
|
|
|
} |
804
|
|
|
|
|
805
|
|
|
|
sub _buildRemovedProteinAnnotation { |
806
|
|
3
|
|
my ($self,$mut,$tran,$wtProt,@classes) = @_; |
807
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new( wt => $wtProt, |
808
|
|
|
|
mt => '-', |
809
|
|
|
|
minpos => 1, |
810
|
|
|
|
minOffset => 0, |
811
|
|
|
|
maxpos => length($wtProt), |
812
|
|
|
|
maxOffset => 0, |
813
|
|
|
|
acc => $tran->getProteinAccession, |
814
|
|
|
|
accversion => $tran->getProteinAccessionVersion, |
815
|
|
|
|
db => $tran->getDatabase, |
816
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
817
|
|
|
|
seqlength => length($wtProt), |
818
|
|
|
|
description => 'p.0', |
819
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getProteinAnnotationContext(), |
820
|
|
|
|
type => $self->_getDefaultProteinAnnotationType(), |
821
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype()); |
822
|
|
|
|
$anno->addClassification(@classes); |
823
|
|
|
|
return $anno; |
824
|
|
|
|
} |
825
|
|
|
|
|
826
|
|
|
|
sub _buildUnknownMRNAAnnotation { |
827
|
|
308
|
|
my ($self,$var,$tran,@classes) = @_; |
828
|
|
|
|
my $anno = Sanger::CGP::Vagrent::Data::Annotation->new(wt => '?', |
829
|
|
|
|
mt => '?', |
830
|
|
|
|
minpos => 0, |
831
|
|
|
|
minOffset => 0, |
832
|
|
|
|
maxpos => 0, |
833
|
|
|
|
maxOffset => 0, |
834
|
|
|
|
acc => $tran->getAccession, |
835
|
|
|
|
accversion => $tran->getAccessionVersion, |
836
|
|
|
|
db => $tran->getDatabase, |
837
|
|
|
|
dbversion => $tran->getDatabaseVersion, |
838
|
|
|
|
seqlength => length($tran->getcDNASeq), |
839
|
|
|
|
description => 'r.?', |
840
|
|
|
|
context => Sanger::CGP::Vagrent::Data::Annotation::getmRNAAnnotationContext(), |
841
|
|
|
|
type => Sanger::CGP::Vagrent::Data::Annotation::getUnknownAnnotationType(), |
842
|
|
|
|
subtype => Sanger::CGP::Vagrent::Data::Annotation::getPositionOffSequenceSubtype()); |
843
|
|
|
|
|
844
|
|
|
|
$anno->addClassification(@classes); |
845
|
|
|
|
return $anno; |
846
|
|
|
|
} |
847
|
|
|
|
|
848
|
|
|
|
sub _isOffsetAConsensusSpliceDistance { |
849
|
|
66
|
|
my ($self,$offset) = @_; |
850
|
|
|
|
foreach my $cf(@CONSENSUS_SPLICE_OFFSETS){ |
851
|
100
|
|
|
if($offset == $cf){ |
852
|
|
|
|
return 1; |
853
|
|
|
|
} |
854
|
|
|
|
} |
855
|
|
|
|
return 0; |
856
|
|
|
|
} |
857
|
|
|
|
|
858
|
|
|
|
sub _getConsesnsusSpliceBeforeBoundry { |
859
|
|
189
|
|
return $CONSENSUS_SPLICE_BEFORE_BOUNDRY; |
860
|
|
|
|
} |
861
|
|
|
|
|
862
|
|
|
|
sub _getConsesnsusSpliceAfterBoundry { |
863
|
|
194
|
|
return $CONSENSUS_SPLICE_AFTER_BOUNDRY; |
864
|
|
|
|
} |
865
|
|
|
|
|
866
|
|
|
|
sub _isIntronicOffsetDistance { |
867
|
|
692
|
|
my ($self,$offset) = @_; |
868
|
100
|
|
|
if(abs($offset) >= $INTRONIC_OFFSET_CUTOFF){ |
869
|
|
|
|
return 1; |
870
|
|
|
|
} |
871
|
|
|
|
return 0; |
872
|
|
|
|
} |
873
|
|
|
|
|
874
|
|
|
|
sub _isWithin5KBOffsetDistance { |
875
|
|
147
|
|
my ($self,$offset) = @_; |
876
|
100
|
|
|
if(abs($offset) <= $UPDOWNSTREAM_5KB_CUTOFF){ |
877
|
|
|
|
return 1; |
878
|
|
|
|
} |
879
|
|
|
|
return 0; |
880
|
|
|
|
} |
881
|
|
|
|
|
882
|
|
|
|
sub getUpDownStream5kbCutoff { |
883
|
|
0
|
0
|
return $UPDOWNSTREAM_5KB_CUTOFF; |
884
|
|
|
|
} |
885
|
|
|
|
|
886
|
|
|
|
sub _isWithin2KBUpstreamOffsetDistance { |
887
|
|
142
|
|
my ($self,$offset) = @_; |
888
|
100
|
|
|
if($offset < 0 && $offset >= $UPSTREAM_2KB_CUTOFF){ |
889
|
|
|
|
return 1; |
890
|
|
|
|
} |
891
|
|
|
|
return 0; |
892
|
|
|
|
} |
893
|
|
|
|
|
894
|
|
|
|
sub getUpStream2kbCutoff { |
895
|
|
0
|
0
|
return $UPSTREAM_2KB_CUTOFF; |
896
|
|
|
|
} |
897
|
|
|
|
|
898
|
|
|
|
sub _isWithin500BPDownstreamOffsetDistance { |
899
|
|
121
|
|
my ($self,$offset) = @_; |
900
|
100
|
|
|
if($offset > 0 && $offset <= $DOWNSTREAM_500BP_CUTOFF){ |
901
|
|
|
|
return 1; |
902
|
|
|
|
} |
903
|
|
|
|
return 0; |
904
|
|
|
|
} |
905
|
|
|
|
|
906
|
|
|
|
sub getDownStream500bpCutoff { |
907
|
|
0
|
0
|
return $DOWNSTREAM_500BP_CUTOFF; |
908
|
|
|
|
} |
909
|
|
|
|
|
910
|
|
|
|
|
911
|
|
|
|
sub _coversStartCodon { |
912
|
|
371
|
|
my ($self,$tran,$anno) = @_; |
913
|
50
|
|
|
unless($tran->isProteinCoding){ |
914
|
|
|
|
# if the transcript isn't protein coding it can't have a start codon |
915
|
|
|
|
return 0; |
916
|
|
|
|
} |
917
|
|
|
|
|
918
|
|
|
|
my ($startMin,$startMax); |
919
|
50
|
|
|
if($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getmRNAAnnotationContext()){ |
|
50
|
|
|
|
920
|
|
|
|
$startMin = $tran->getCdsMinPos; |
921
|
|
|
|
$startMax = $tran->getCdsMinPos + 2; |
922
|
|
|
|
} elsif($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext()){ |
923
|
|
|
|
$startMin = 1; |
924
|
|
|
|
$startMax = 3; |
925
|
|
|
|
} else { |
926
|
|
|
|
# don't know, assume no |
927
|
|
|
|
return 0; |
928
|
|
|
|
} |
929
|
|
|
|
|
930
|
100
|
|
|
if($anno->hasClassification($self->getInsertionClass)){ |
931
|
|
|
|
# insertions are a special case, coordinates are outside the variant |
932
|
50
|
|
|
if($anno->getMinPos < $startMax && $anno->getMaxPos > $startMin){ |
933
|
|
|
|
# var started before the end of the first codon, and ended after the start of the first codon |
934
|
|
|
|
return 1; |
935
|
|
|
|
} |
936
|
|
|
|
} else { |
937
|
100
|
|
|
if(($anno->getMinPos < $startMax || ($anno->getMinPos == $startMax && $anno->getMinOffset == 0)) && |
938
|
|
|
|
($anno->getMaxPos > $startMin || ($anno->getMaxPos == $startMin && $anno->getMaxOffset == 0))){ |
939
|
|
|
|
# var started before the end of the first codon OR explicitly on the last base of the first codon AND |
940
|
|
|
|
# var ended after the start of the first codon OR explicitly on the first base of the first codon |
941
|
|
|
|
return 1; |
942
|
|
|
|
} |
943
|
|
|
|
} |
944
|
|
|
|
return 0; |
945
|
|
|
|
} |
946
|
|
|
|
|
947
|
|
|
|
sub _coversStopCodon { |
948
|
|
371
|
|
my ($self,$tran,$anno) = @_; |
949
|
50
|
|
|
unless($tran->isProteinCoding){ |
950
|
|
|
|
# if the transcript isn't protein coding it can't have a stop codon |
951
|
|
|
|
return 0; |
952
|
|
|
|
} |
953
|
|
|
|
my ($stopMin,$stopMax); |
954
|
50
|
|
|
if($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getmRNAAnnotationContext()){ |
|
50
|
|
|
|
955
|
|
|
|
$stopMin = $tran->getCdsMaxPos - 2; |
956
|
|
|
|
$stopMax = $tran->getCdsMaxPos; |
957
|
|
|
|
} elsif($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext()){ |
958
|
|
|
|
$stopMin = $tran->getCdsLength - 2; |
959
|
|
|
|
$stopMax = $tran->getCdsLength; |
960
|
|
|
|
} else { |
961
|
|
|
|
# don't know, assume no |
962
|
|
|
|
return 0; |
963
|
|
|
|
} |
964
|
|
|
|
|
965
|
100
|
|
|
if($anno->hasClassification($self->getInsertionClass)){ |
966
|
|
|
|
# insertions are a special case, coordinates are outside the variant |
967
|
50
|
|
|
if($anno->getMinPos < $stopMax && $anno->getMaxPos > $stopMin){ |
968
|
|
|
|
# var started before the end of the last codon, and ended after the start of the last codon |
969
|
|
|
|
return 1; |
970
|
|
|
|
} |
971
|
|
|
|
} else { |
972
|
100
|
|
|
if(($anno->getMinPos < $stopMax || ($anno->getMinPos == $stopMax && $anno->getMinOffset == 0)) && |
973
|
|
|
|
($anno->getMaxPos > $stopMin || ($anno->getMaxPos == $stopMin && $anno->getMaxOffset == 0))){ |
974
|
|
|
|
# var started before the end of the last codon OR explicitly on the last base of the last codon AND |
975
|
|
|
|
# var ended after the start of the last codon OR explicitly on the first base of the last codon |
976
|
|
|
|
return 1; |
977
|
|
|
|
} |
978
|
|
|
|
} |
979
|
|
|
|
return 0; |
980
|
|
|
|
} |
981
|
|
|
|
|
982
|
|
|
|
sub _getTranscriptSource { |
983
|
|
862
|
|
return shift->{_transcriptSource}; |
984
|
|
|
|
} |
985
|
|
|
|
|
986
|
|
|
|
sub _calculateCdsTranslationPadStrings { |
987
|
|
441
|
|
my ($self,$tran) = @_; |
988
|
|
|
|
my $prePad = ''; |
989
|
|
|
|
my $postPad = ''; |
990
|
50
|
|
|
if($tran->getCdsPhase == 0){ |
|
0
|
|
|
|
991
|
|
|
|
# nothing to pad |
992
|
|
|
|
$prePad = ''; |
993
|
|
|
|
} elsif($tran->getCdsPhase > 0 && $tran->getCdsPhase < 3){ |
994
|
0
|
|
|
if($tran->getCdsPhase == 1){ |
|
0
|
|
|
|
995
|
|
|
|
$prePad = 'N'; |
996
|
|
|
|
} elsif ($tran->getCdsPhase == 2){ |
997
|
|
|
|
$prePad = 'NN'; |
998
|
|
|
|
} else { |
999
|
|
|
|
$self->throw('this should be impossible'); |
1000
|
|
|
|
} |
1001
|
|
|
|
} else { |
1002
|
|
|
|
warn Dumper($tran); |
1003
|
|
|
|
$self->throw("Unhandled phase"); |
1004
|
|
|
|
} |
1005
|
|
|
|
|
1006
|
50
|
|
|
if(length($prePad . $tran->getCdsSeq) % 3 == 0){ |
1007
|
|
|
|
# nothing to pad |
1008
|
|
|
|
$postPad = ''; |
1009
|
|
|
|
} else { |
1010
|
|
|
|
# yuk, its not a round number of codons long, got to pad the end. |
1011
|
|
|
|
my $rem = 3 - (length($prePad . $tran->getCdsSeq) % 3); |
1012
|
|
|
|
for(my $i = 0 ; $i < $rem; $i++){ |
1013
|
|
|
|
$postPad .= 'N'; |
1014
|
|
|
|
} |
1015
|
|
|
|
} |
1016
|
|
|
|
return ($prePad,$postPad); |
1017
|
|
|
|
} |
1018
|
|
|
|
|
1019
|
|
|
|
sub _canAnnotateToCDS { |
1020
|
|
441
|
|
my ($self,$tran,$anno) = @_; |
1021
|
50
|
|
|
unless($tran->isProteinCoding){ |
1022
|
|
|
|
# if the transcript isn't protein coding it can't be a coding change |
1023
|
|
|
|
return 0; |
1024
|
|
|
|
} |
1025
|
50
|
|
|
if($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getmRNAAnnotationContext()){ |
1026
|
|
|
|
# first work out if the variant overlaps with the CDS |
1027
|
100
|
|
|
if($anno->hasClassification($self->getInsertionClass)){ |
1028
|
|
|
|
# insertions are a special case. |
1029
|
|
|
|
# Coordinates are the last WT positions, and not the first variant ones like everything else |
1030
|
|
|
|
|
1031
|
50
|
|
|
print 'ANNO POS: '.$anno->getMinPos.' , '.$anno->getMinOffset.' - '.$anno->getMaxPos.' , '.$anno->getMaxOffset."\n" if $self->_debug(); |
1032
|
50
|
|
|
print 'CDS POS: '.$tran->getCdsMinPos.' , '.$tran->getCdsMaxPos."\n" if $self->_debug(); |
1033
|
|
|
|
|
1034
|
100
|
|
|
if($anno->getMaxPos < $tran->getCdsMinPos || $anno->getMinPos > $tran->getCdsMaxPos){ |
|
100
|
|
|
|
1035
|
|
|
|
# ends before CDS or starts afterwards |
1036
|
|
|
|
return 0; |
1037
|
|
|
|
} elsif($anno->getMaxPos == $tran->getCdsMinPos) { |
1038
|
|
|
|
# potential start codon issues |
1039
|
100
|
|
|
if($anno->getMinPos == $anno->getMaxPos && $anno->getMinPos == $tran->getCdsMinPos && abs($anno->getMinOffset) + abs($anno->getMaxOffset) > 0){ |
1040
|
|
|
|
# probably start coordinate issues |
1041
|
50
|
|
|
unless($anno->getMaxOffset <= 0 && $self->_isIntronicOffsetDistance($anno->getMaxOffset) == 0){ |
1042
|
|
|
|
# or not |
1043
|
|
|
|
return 0; |
1044
|
|
|
|
} |
1045
|
|
|
|
} else { |
1046
|
|
|
|
return 0; |
1047
|
|
|
|
} |
1048
|
|
|
|
} |
1049
|
|
|
|
} else { |
1050
|
100
|
|
|
if($anno->getMaxPos < $tran->getCdsMinPos || $anno->getMinPos > $tran->getCdsMaxPos){ |
1051
|
|
|
|
# its outside the CDS |
1052
|
|
|
|
return 0; |
1053
|
|
|
|
} |
1054
|
|
|
|
} |
1055
|
|
|
|
# now we look at the classifications to workout if can be annotated to the CDS |
1056
|
100
|
|
|
if($anno->hasClassification($self->getSpliceRegionVariantClass) || $anno->hasClassification($self->getEssentialSpliceSiteVariantClass)){ |
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
|
50
|
|
|
|
|
50
|
|
|
|
|
100
|
|
|
|
1057
|
|
|
|
return 1; |
1058
|
|
|
|
} elsif($anno->hasClassification($self->getComplexChangeVariantClass)){ |
1059
|
|
|
|
return 1; |
1060
|
|
|
|
} elsif($anno->hasClassification($self->getInFrameVariantClass)){ |
1061
|
|
|
|
return 1; |
1062
|
|
|
|
} elsif($anno->hasClassification($self->getFrameShiftVariantClass)){ |
1063
|
|
|
|
return 1; |
1064
|
|
|
|
} elsif($anno->hasClassification($self->getCodonVariantClass)){ |
1065
|
|
|
|
return 1; |
1066
|
|
|
|
} elsif($anno->hasClassification($self->getIntronVariantClass)){ |
1067
|
|
|
|
return 0; |
1068
|
|
|
|
} elsif($anno->hasClassification($self->getUnknownVariantClass)){ |
1069
|
|
|
|
return 0; |
1070
|
|
|
|
} elsif($anno->hasClassification($self->getInsertionClass) && $anno->hasClassification($self->get5PrimeUtrVariantClass)){ |
1071
|
|
|
|
# odd case, insertions close to the start codons can be described on the CDS even though they don't change it. |
1072
|
|
|
|
return 1; |
1073
|
|
|
|
} else { |
1074
|
|
|
|
my $msg = "Unable to calculate CDS relevance - UNKNOWN CLASSIFICATION: ".join(' ',$anno->getClassifications); |
1075
|
|
|
|
$self->addMessage($msg); |
1076
|
|
|
|
$log->info($msg); |
1077
|
|
|
|
return 0; |
1078
|
|
|
|
} |
1079
|
|
|
|
} else { |
1080
|
|
|
|
my $msg = "Unable to calculate CDS relevance - UNKNOWN CONTEXT: ".$anno->getContext; |
1081
|
|
|
|
$self->addMessage($msg); |
1082
|
|
|
|
$log->info($msg); |
1083
|
|
|
|
return 0; |
1084
|
|
|
|
} |
1085
|
|
|
|
} |
1086
|
|
|
|
|
1087
|
|
|
|
sub _canAnnotateToProtein { |
1088
|
|
441
|
|
my ($self,$tran,$anno) = @_; |
1089
|
|
|
|
|
1090
|
50
|
|
|
unless($tran->isProteinCoding){ |
1091
|
|
|
|
# if the transcript isn't protein coding it can't be a coding change |
1092
|
|
|
|
return 0; |
1093
|
|
|
|
} |
1094
|
50
|
|
|
if($anno->getContext eq Sanger::CGP::Vagrent::Data::Annotation::getCDSAnnotationContext()){ |
1095
|
100
|
|
|
if($anno->hasClassification($self->getUnknownVariantClass)){ |
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
|
100
|
|
|
|
1096
|
|
|
|
return 0; |
1097
|
|
|
|
} elsif($anno->hasClassification($self->getEssentialSpliceSiteVariantClass)){ |
1098
|
|
|
|
return 0; |
1099
|
|
|
|
} elsif($anno->hasClassification($self->getSpliceRegionVariantClass)){ |
1100
|
|
|
|
return 0; |
1101
|
|
|
|
} elsif($anno->hasClassification($self->getComplexChangeVariantClass)){ |
1102
|
|
|
|
return 0; |
1103
|
|
|
|
} elsif($anno->hasClassification($self->getInFrameVariantClass)){ |
1104
|
|
|
|
return 1; |
1105
|
|
|
|
} elsif($anno->hasClassification($self->getFrameShiftVariantClass)){ |
1106
|
|
|
|
return 1; |
1107
|
|
|
|
} elsif($anno->hasClassification($self->getCodonVariantClass)){ |
1108
|
|
|
|
return 1; |
1109
|
|
|
|
} else { |
1110
|
|
|
|
my $msg = "Unable to calculate protein relevance - UNKNOWN CLASSIFICATION: ".join(' ',$anno->getClassifications); |
1111
|
|
|
|
$self->addMessage($msg); |
1112
|
|
|
|
$log->info($msg); |
1113
|
|
|
|
return 0; |
1114
|
|
|
|
} |
1115
|
|
|
|
} else { |
1116
|
|
|
|
my $msg = "Unable to calculate protein relevance - UNKNOWN CONTEXT: ".$anno->getContext; |
1117
|
|
|
|
$self->addMessage($msg); |
1118
|
|
|
|
$log->info($msg); |
1119
|
|
|
|
return 0; |
1120
|
|
|
|
} |
1121
|
|
|
|
} |
1122
|
|
|
|
|
1123
|
|
|
|
sub _revcompSeq { |
1124
|
|
487
|
|
my ($self,$seqIn) = @_; |
1125
|
|
|
|
my $seqOut; |
1126
|
|
|
|
foreach my $b(reverse(split('',$seqIn))){ |
1127
|
|
|
|
$b =~ tr/atcgATCG/tagcTAGC/; |
1128
|
|
|
|
$seqOut .= $b; |
1129
|
|
|
|
} |
1130
|
|
|
|
return $seqOut; |
1131
|
|
|
|
} |
1132
|
|
|
|
|
1133
|
|
|
|
sub _sequenceStartsWithSequence { |
1134
|
|
26
|
|
my ($self,$seqRef,$seqCheck) = @_; |
1135
|
50
|
|
|
warn "CHECKING IF\n$seqRef\nSTARTS WITH\n$seqCheck\n" if ($self->_debug); |
1136
|
50
|
|
|
if(length($seqRef) < length($seqCheck)){ |
1137
|
0
|
|
|
warn "FALSE\n" if ($self->_debug); |
1138
|
|
|
|
return 0; |
1139
|
|
|
|
} |
1140
|
50
|
|
|
warn substr($seqRef,0,length($seqCheck))."\n" if ($self->_debug); |
1141
|
50
|
|
|
warn $seqCheck."\n" if ($self->_debug); |
1142
|
|
|
|
|
1143
|
50
|
|
|
if(substr($seqRef,0,length($seqCheck)) eq $seqCheck){ |
1144
|
0
|
|
|
warn "TRUE\n" if ($self->_debug); |
1145
|
|
|
|
return 1; |
1146
|
|
|
|
} |
1147
|
50
|
|
|
warn "FALSE\n" if ($self->_debug); |
1148
|
|
|
|
return 0; |
1149
|
|
|
|
} |
1150
|
|
|
|
|
1151
|
|
|
|
sub _calculateFrameShiftProteinChange { |
1152
|
|
26
|
|
my ($self,$wtProt,$mtProt) = @_; |
1153
|
|
|
|
my $subtype = Sanger::CGP::Vagrent::Data::Annotation::getPositionKnownSubtype(); |
1154
|
|
|
|
my $wt = undef; |
1155
|
|
|
|
my $mt = undef; |
1156
|
|
|
|
my $mutProtMin = undef; |
1157
|
|
|
|
my $mutProtMax = undef; |
1158
|
|
|
|
my $desc = undef; |
1159
|
50
|
|
|
warn "\n$wtProt\n$mtProt\n" if ($self->_debug); |
1160
|
|
|
|
for(my $i = 0 ; $i < length($mtProt); $i++){ |
1161
|
50
|
|
|
warn "$wt, ".substr($wtProt,$i,1)." ne ".substr($mtProt,$i,1)."\n" if ($self->_debug); |
1162
|
100
|
|
|
if(!defined($wt) && substr($wtProt,$i,1) ne substr($mtProt,$i,1)){ |
|
50
|
|
|
|
|
50
|
|
|
|
|
100
|
|
|
|
1163
|
|
|
|
$wt = substr($wtProt,$i,1); |
1164
|
|
|
|
$mt = substr($mtProt,$i,1); |
1165
|
|
|
|
$mutProtMin = $i + 1; |
1166
|
|
|
|
$mutProtMax = $mutProtMin; |
1167
|
100
|
|
|
if($mt eq '*'){ |
1168
|
|
|
|
# variation actually creates the stop codon |
1169
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'fs*1'; |
1170
|
|
|
|
last; |
1171
|
|
|
|
} else { |
1172
|
|
|
|
# we'll reserve an I don't know description, should get overridden in further iterations. |
1173
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'fs?'; |
1174
|
|
|
|
} |
1175
|
|
|
|
} elsif(!defined($wt) && length($mtProt) == $i + 1 && length($wtProt) > $i + 1 && substr($wtProt,$i,1) eq substr($mtProt,$i,1)){ |
1176
|
|
|
|
# interesting case, the current position is the last position of the mutant protein |
1177
|
|
|
|
# no differences have been found between mt and wt, but the wt sequence is longer, ie we have lost residues from the end |
1178
|
|
|
|
$wt = substr($wtProt,($i + 1),1); |
1179
|
|
|
|
$mt = '?'; |
1180
|
|
|
|
$mutProtMin = $i + 2; |
1181
|
|
|
|
$mutProtMax = $mutProtMin; |
1182
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'fs?'; |
1183
|
|
|
|
last; |
1184
|
|
|
|
} elsif(defined($wt) && length($mtProt) == $i + 1 && substr($mtProt,$i,1) ne '*'){ |
1185
|
|
|
|
# this is the last base of the mutant protein and we never reach a stop. |
1186
|
|
|
|
$mt .= substr($mtProt,$i,1); |
1187
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'fs*>'.length($mt); |
1188
|
|
|
|
last; |
1189
|
|
|
|
} elsif(defined($wt)){ |
1190
|
|
|
|
$mt .= substr($mtProt,$i,1); |
1191
|
100
|
|
|
if(substr($mtProt,$i,1) eq '*'){ |
1192
|
|
|
|
$desc = 'p.'.$wt.$mutProtMin.'fs*'.length($mt); |
1193
|
|
|
|
last; |
1194
|
|
|
|
} |
1195
|
|
|
|
} |
1196
|
|
|
|
} |
1197
|
50
|
|
|
warn "$subtype,$wt,$mt,$mutProtMin,$mutProtMax,$desc\n" if ($self->_debug); |
1198
|
|
|
|
return ($subtype,$wt,$mt,$mutProtMin,$mutProtMax,$desc); |
1199
|
|
|
|
} |
1200
|
|
|
|
|
1201
|
|
|
|
sub _calculateGenomicCdsPosition { |
1202
|
|
14
|
|
my ($self,$tran) = @_; |
1203
|
|
|
|
my @exons = $tran->getExonsGenomicOrder; |
1204
|
|
|
|
my $genoCdsMin = undef; |
1205
|
|
|
|
my $genoCdsMax = undef; |
1206
|
|
|
|
foreach my $e(@exons){ |
1207
|
100
|
|
|
if($tran->getStrand == 1){ |
1208
|
100
|
|
|
if(!defined($genoCdsMin)){ |
1209
|
100
|
|
|
if($e->getRnaMinPos <= $tran->getCdsMinPos && $e->getRnaMaxPos >= $tran->getCdsMinPos){ |
1210
|
|
|
|
$genoCdsMin = $e->getMinPos + ($tran->getCdsMinPos - $e->getRnaMinPos); |
1211
|
|
|
|
} |
1212
|
|
|
|
} |
1213
|
50
|
|
|
if(!defined($genoCdsMax)){ |
1214
|
100
|
|
|
if($e->getRnaMinPos <= $tran->getCdsMaxPos && $e->getRnaMaxPos >= $tran->getCdsMaxPos){ |
1215
|
|
|
|
$genoCdsMax = $e->getMinPos + ($tran->getCdsMaxPos - $e->getRnaMinPos); |
1216
|
|
|
|
} |
1217
|
|
|
|
} |
1218
|
|
|
|
} else { |
1219
|
100
|
|
|
if(!defined($genoCdsMin)){ |
1220
|
50
|
|
|
if($e->getRnaMinPos <= $tran->getCdsMaxPos && $e->getRnaMaxPos >= $tran->getCdsMaxPos){ |
1221
|
|
|
|
$genoCdsMin = $e->getMaxPos - ($tran->getCdsMaxPos - $e->getRnaMinPos); |
1222
|
|
|
|
} |
1223
|
|
|
|
} |
1224
|
100
|
|
|
if(!defined($genoCdsMax)){ |
1225
|
100
|
|
|
if($e->getRnaMinPos <= $tran->getCdsMinPos && $e->getRnaMaxPos >= $tran->getCdsMinPos){ |
1226
|
|
|
|
$genoCdsMax = $e->getMaxPos - ($tran->getCdsMinPos - $e->getRnaMinPos); |
1227
|
|
|
|
} |
1228
|
|
|
|
} |
1229
|
|
|
|
} |
1230
|
|
|
|
} |
1231
|
|
|
|
return ($genoCdsMin,$genoCdsMax); |
1232
|
|
|
|
} |
1233
|
|
|
|
|
1234
|
|
|
|
sub _arrayHasString { |
1235
|
|
605
|
|
my ($self,$val,@arr) = @_; |
1236
|
|
|
|
foreach my $a (@arr){ |
1237
|
100
|
|
|
return 1 if $a eq $val; |
1238
|
|
|
|
} |
1239
|
|
|
|
return 0; |
1240
|
|
|
|
} |
1241
|
|
|
|
|
1242
|
|
|
|
sub _defaultTranscriptSort { |
1243
|
|
0
|
|
my ($self,@trans) = @_; |
1244
|
|
|
|
my $customSort = sub { |
1245
|
|
0
|
|
my $accds = 0; |
1246
|
|
|
|
my $bccds = 0; |
1247
|
0
|
|
|
$accds = 1 if(defined $a->getCCDS && length($a->getCCDS) > 0); |
1248
|
0
|
|
|
$bccds = 1 if(defined $b->getCCDS && length($b->getCCDS) > 0); |
1249
|
|
|
|
my $chk = $bccds <=> $accds; |
1250
|
0
|
|
|
if($chk == 0){ |
1251
|
|
|
|
$chk = $b->getCdsLength <=> $a->getCdsLength; |
1252
|
0
|
|
|
if($chk == 0){ |
1253
|
|
|
|
$chk = length($b->getcDNASeq()) <=> length($a->getcDNASeq()); |
1254
|
|
|
|
} |
1255
|
|
|
|
} |
1256
|
|
|
|
return $chk;}; |
1257
|
|
|
|
return sort $customSort @trans; |
1258
|
|
|
|
} |
1259
|
|
|
|
|
1260
|
|
|
|
__END__ |
1261
|
|
|
|
|
1262
|
|
|
|
=head1 NAME |
1263
|
|
|
|
|
1264
|
|
|
|
Sanger::CGP::Vagrent::Annotators::AbstractAnnotator - Abstract base class for the annotation generators |
1265
|
|
|
|
|
1266
|
|
|
|
=head1 DESCRIPTION |
1267
|
|
|
|
|
1268
|
|
|
|
This is an abstract template class for the mutation annotators, it provides a lot of shared behind the scenes functionality. All |
1269
|
|
|
|
subclasses must implement the _getAnnotation method. |
1270
|
|
|
|
|
1271
|
|
|
|
=head1 METHODS |
1272
|
|
|
|
|
1273
|
|
|
|
=head2 Constructor |
1274
|
|
|
|
|
1275
|
|
|
|
=head3 new |
1276
|
|
|
|
|
1277
|
|
|
|
=over |
1278
|
|
|
|
|
1279
|
|
|
|
=item Usage : |
1280
|
|
|
|
|
1281
|
|
|
|
my $source = Sanger::CGP::Vagrent::Annotators::AbstractAnnotatorSubClass->new(%params); |
1282
|
|
|
|
|
1283
|
|
|
|
=item Function : |
1284
|
|
|
|
|
1285
|
|
|
|
Builds a new Sanger::CGP::Vagrent::Annotators::AbstractAnnotator inheriting object |
1286
|
|
|
|
|
1287
|
|
|
|
=item Returns : |
1288
|
|
|
|
|
1289
|
|
|
|
Sanger::CGP::Vagrent::Annotators::AbstractAnnotator object initialized with parameter values |
1290
|
|
|
|
|
1291
|
|
|
|
=item Params : |
1292
|
|
|
|
|
1293
|
|
|
|
Hash of parameter values |
1294
|
|
|
|
|
1295
|
|
|
|
transcriptSource => A Sanger::CGP::Vagrent::TranscriptSource::AbstractTranscriptSource inheriting object |
1296
|
|
|
|
bookmarker => (Optional) An array reference of, or single, Sanger::CGP::Vagrent::Bookmarkers::AbstractBookmarker inheriting object |
1297
|
|
|
|
only_bookmarked => (Optional) Boolean, only return annotations that get bookmarked |
1298
|
|
|
|
|
1299
|
|
|
|
=back |
1300
|
|
|
|
|
1301
|
|
|
|
=head2 Functions |
1302
|
|
|
|
|
1303
|
|
|
|
=head3 getAnnotation |
1304
|
|
|
|
|
1305
|
|
|
|
=over |
1306
|
|
|
|
|
1307
|
|
|
|
=item Usage : |
1308
|
|
|
|
|
1309
|
|
|
|
my @annoGrps = $annotator->getAnnotation($variation); |
1310
|
|
|
|
|
1311
|
|
|
|
=item Function : |
1312
|
|
|
|
|
1313
|
|
|
|
Annotates the supplied L<Variation|Sanger::CGP::Vagrent::Data::AbstractVariation> object and returns a list of L<AnnotationGroups|Sanger::CGP::Vagrent::Data::AnnotationGroup> objects. |
1314
|
|
|
|
If L<Bookmarkers|Sanger::CGP::Vagrent::Bookmarkers::AbstractBookmarker> have been set, the AnnotationGroups will have been marked before being returned. |
1315
|
|
|
|
If 'only_bookmarked' was set to true, only AnnotationGroups that match Bookmarkers will be returned. |
1316
|
|
|
|
|
1317
|
|
|
|
=item Returns : |
1318
|
|
|
|
|
1319
|
|
|
|
An array of L<Sanger::CGP::Vagrent::Data::AnnotationGroup|Sanger::CGP::Vagrent::Data::AnnotationGroup> objects |
1320
|
|
|
|
|
1321
|
|
|
|
=item Params : |
1322
|
|
|
|
|
1323
|
|
|
|
A L<Sanger::CGP::Vagrent::Data::AbstractVariation|Sanger::CGP::Vagrent::Data::AbstractVariation> implementing object |
1324
|
|
|
|
|
1325
|
|
|
|
=back |
1326
|
|
|
|
|
1327
|
|
|
|
=head3 addMessage |
1328
|
|
|
|
|
1329
|
|
|
|
=over |
1330
|
|
|
|
|
1331
|
|
|
|
=item Usage : |
1332
|
|
|
|
|
1333
|
|
|
|
$annotator->addMessage("Interesting event found"); |
1334
|
|
|
|
|
1335
|
|
|
|
=item Function : |
1336
|
|
|
|
|
1337
|
|
|
|
Adds a text message to the message list. All messages are reset every time C<getAnnotation> is called |
1338
|
|
|
|
|
1339
|
|
|
|
=item Returns : |
1340
|
|
|
|
|
1341
|
|
|
|
Nothing |
1342
|
|
|
|
|
1343
|
|
|
|
=item Params : |
1344
|
|
|
|
|
1345
|
|
|
|
String |
1346
|
|
|
|
|
1347
|
|
|
|
=back |
1348
|
|
|
|
|
1349
|
|
|
|
=head3 getMessages |
1350
|
|
|
|
|
1351
|
|
|
|
=over |
1352
|
|
|
|
|
1353
|
|
|
|
=item Usage : |
1354
|
|
|
|
|
1355
|
|
|
|
my @mess = $annotator->getMessages(); |
1356
|
|
|
|
|
1357
|
|
|
|
=item Function : |
1358
|
|
|
|
|
1359
|
|
|
|
Retrieves a list of message strings about the most recent annotation attempt |
1360
|
|
|
|
|
1361
|
|
|
|
=item Returns : |
1362
|
|
|
|
|
1363
|
|
|
|
Array of String |
1364
|
|
|
|
|
1365
|
|
|
|
=back |
1366
|
|
|
|
|
1367
|
|
|
|
=head2 Abstract |
1368
|
|
|
|
|
1369
|
|
|
|
=head3 _getAnnotation |
1370
|
|
|
|
|
1371
|
|
|
|
=over |
1372
|
|
|
|
|
1373
|
|
|
|
=item Usage : |
1374
|
|
|
|
|
1375
|
|
|
|
my $type = $annotator->_getAnnotation($variation); |
1376
|
|
|
|
|
1377
|
|
|
|
=item Function : |
1378
|
|
|
|
|
1379
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns a list of L<AnnotationGroups|Sanger::CGP::Vagrent::Data::AnnotationGroup> |
1380
|
|
|
|
|
1381
|
|
|
|
=item Returns : |
1382
|
|
|
|
|
1383
|
|
|
|
An array of L<Sanger::CGP::Vagrent::Data::AnnotationGroup|Sanger::CGP::Vagrent::Data::AnnotationGroup> objects |
1384
|
|
|
|
|
1385
|
|
|
|
=item Params : |
1386
|
|
|
|
|
1387
|
|
|
|
A L<Sanger::CGP::Vagrent::Data::AbstractVariation|Sanger::CGP::Vagrent::Data::AbstractVariation> implementing object |
1388
|
|
|
|
|
1389
|
|
|
|
=back |
1390
|
|
|
|
|
1391
|
|
|
|
=head3 _getDefaultCDSAnnotationType |
1392
|
|
|
|
|
1393
|
|
|
|
=over |
1394
|
|
|
|
|
1395
|
|
|
|
=item Usage : |
1396
|
|
|
|
|
1397
|
|
|
|
my $type = $annotator->_getDefaultCDSAnnotationType(); |
1398
|
|
|
|
|
1399
|
|
|
|
=item Function : |
1400
|
|
|
|
|
1401
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns default CDS annotation (L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> type constant) type for the Annotator |
1402
|
|
|
|
|
1403
|
|
|
|
=item Returns : |
1404
|
|
|
|
|
1405
|
|
|
|
String - L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> type constant |
1406
|
|
|
|
|
1407
|
|
|
|
=back |
1408
|
|
|
|
|
1409
|
|
|
|
=head3 _getMutatedCdsSequence |
1410
|
|
|
|
|
1411
|
|
|
|
=over |
1412
|
|
|
|
|
1413
|
|
|
|
=item Usage : |
1414
|
|
|
|
|
1415
|
|
|
|
my $varSeq = $annotator->_getMutatedCdsSequence(); |
1416
|
|
|
|
|
1417
|
|
|
|
=item Function : |
1418
|
|
|
|
|
1419
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns the full variant form of the CDS sequence |
1420
|
|
|
|
|
1421
|
|
|
|
=item Returns : |
1422
|
|
|
|
|
1423
|
|
|
|
String, DNA sequence |
1424
|
|
|
|
|
1425
|
|
|
|
=item Params : |
1426
|
|
|
|
|
1427
|
|
|
|
String - Full wildtype CDS DNA sequence |
1428
|
|
|
|
Integer - Minimum position of the variant on the wildtype CDS sequence |
1429
|
|
|
|
Integer - Maximum position of the variant on the wildtype CDS sequence |
1430
|
|
|
|
String - Mutant DNA sequence for the variant |
1431
|
|
|
|
|
1432
|
|
|
|
=back |
1433
|
|
|
|
|
1434
|
|
|
|
=head3 _getWildTypeStringForCDSAnno |
1435
|
|
|
|
|
1436
|
|
|
|
=over |
1437
|
|
|
|
|
1438
|
|
|
|
=item Usage : |
1439
|
|
|
|
|
1440
|
|
|
|
my $wtseq = $annotator->_getWildTypeStringForCDSAnno($var,$tran,$mrnaAnno); |
1441
|
|
|
|
|
1442
|
|
|
|
=item Function : |
1443
|
|
|
|
|
1444
|
|
|
|
Abstract internal function, must be implemented in subclass. Generates the CDS wildtype string from the mRNA annotation |
1445
|
|
|
|
|
1446
|
|
|
|
=item Returns : |
1447
|
|
|
|
|
1448
|
|
|
|
String, DNA sequence |
1449
|
|
|
|
|
1450
|
|
|
|
=item Params : |
1451
|
|
|
|
|
1452
|
|
|
|
A Sanger::CGP::Vagrent::Data::AbstractVariation implementing object |
1453
|
|
|
|
A Sanger::CGP::Vagrent::Data::Transcript object |
1454
|
|
|
|
A Sanger::CGP::Vagrent::Data::Annotation object |
1455
|
|
|
|
|
1456
|
|
|
|
=back |
1457
|
|
|
|
|
1458
|
|
|
|
=head3 _getMutantStringForCDSAnno |
1459
|
|
|
|
|
1460
|
|
|
|
=over |
1461
|
|
|
|
|
1462
|
|
|
|
=item Usage : |
1463
|
|
|
|
|
1464
|
|
|
|
my $varseq = $annotator->_getMutantStringForCDSAnno($var,$tran,$mrnaAnno); |
1465
|
|
|
|
|
1466
|
|
|
|
=item Function : |
1467
|
|
|
|
|
1468
|
|
|
|
Abstract internal function, must be implemented in subclass. Generates the CDS variant string from the mRNA annotation |
1469
|
|
|
|
|
1470
|
|
|
|
=item Returns : |
1471
|
|
|
|
|
1472
|
|
|
|
String, DNA sequence |
1473
|
|
|
|
|
1474
|
|
|
|
=item Params : |
1475
|
|
|
|
|
1476
|
|
|
|
A Sanger::CGP::Vagrent::Data::AbstractVariation implementing object |
1477
|
|
|
|
A Sanger::CGP::Vagrent::Data::Transcript object |
1478
|
|
|
|
A Sanger::CGP::Vagrent::Data::Annotation object |
1479
|
|
|
|
|
1480
|
|
|
|
=back |
1481
|
|
|
|
|
1482
|
|
|
|
=head3 _getCDSDescriptionString |
1483
|
|
|
|
|
1484
|
|
|
|
=over |
1485
|
|
|
|
|
1486
|
|
|
|
=item Usage : |
1487
|
|
|
|
|
1488
|
|
|
|
my $desc = $annotator->_getCDSDescriptionString($tran,$cdsMin,$cdsMax,$cdsMinOffset,$cdsMaxOffset,$wt,$mt); |
1489
|
|
|
|
|
1490
|
|
|
|
=item Function : |
1491
|
|
|
|
|
1492
|
|
|
|
Abstract internal function, must be implemented in subclass. Takes the plotted CDS variation data and returns the HGVS syntax describing the change |
1493
|
|
|
|
|
1494
|
|
|
|
=item Returns : |
1495
|
|
|
|
|
1496
|
|
|
|
String, HGVS description |
1497
|
|
|
|
|
1498
|
|
|
|
=item Params : |
1499
|
|
|
|
|
1500
|
|
|
|
A Sanger::CGP::Vagrent::Data::Transcript object |
1501
|
|
|
|
Integer - CDS minimum position |
1502
|
|
|
|
Integer - CDS maximum position |
1503
|
|
|
|
Integer - Offset from the CDS minimum position (signed) |
1504
|
|
|
|
Integer - Offset from the CDS maximum position (signed) |
1505
|
|
|
|
String - Wildtype cDNA sequence of variant |
1506
|
|
|
|
String - Variant cDNA sequence of variant |
1507
|
|
|
|
|
1508
|
|
|
|
=back |
1509
|
|
|
|
|
1510
|
|
|
|
=head3 _getDefaultProteinAnnotationType |
1511
|
|
|
|
|
1512
|
|
|
|
=over |
1513
|
|
|
|
|
1514
|
|
|
|
=item Usage : |
1515
|
|
|
|
|
1516
|
|
|
|
my $type = $annotator->_getDefaultProteinAnnotationType(); |
1517
|
|
|
|
|
1518
|
|
|
|
=item Function : |
1519
|
|
|
|
|
1520
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns default Protein annotation (L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> type constant) type for the Annotator |
1521
|
|
|
|
|
1522
|
|
|
|
=item Returns : |
1523
|
|
|
|
|
1524
|
|
|
|
String - L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> type constant |
1525
|
|
|
|
|
1526
|
|
|
|
=back |
1527
|
|
|
|
|
1528
|
|
|
|
=head3 _getCdsMinPosForProteinCalculation |
1529
|
|
|
|
|
1530
|
|
|
|
=over |
1531
|
|
|
|
|
1532
|
|
|
|
=item Usage : |
1533
|
|
|
|
|
1534
|
|
|
|
my $max = $annotator->_getCdsMinPosForProteinCalculation($cDNAAnnot); |
1535
|
|
|
|
|
1536
|
|
|
|
=item Function : |
1537
|
|
|
|
|
1538
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns the minimum cDNA location of the variant that can be used for protein annotation |
1539
|
|
|
|
|
1540
|
|
|
|
=item Returns : |
1541
|
|
|
|
|
1542
|
|
|
|
Integer - cDNA position |
1543
|
|
|
|
|
1544
|
|
|
|
=item Params : |
1545
|
|
|
|
|
1546
|
|
|
|
A L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> representing the cDNA annotation |
1547
|
|
|
|
|
1548
|
|
|
|
=back |
1549
|
|
|
|
|
1550
|
|
|
|
=head3 _getCdsMaxPosForProteinCalculation |
1551
|
|
|
|
|
1552
|
|
|
|
=over |
1553
|
|
|
|
|
1554
|
|
|
|
=item Usage : |
1555
|
|
|
|
|
1556
|
|
|
|
my $max = $annotator->_getCdsMaxPosForProteinCalculation($cDNAAnnot); |
1557
|
|
|
|
|
1558
|
|
|
|
=item Function : |
1559
|
|
|
|
|
1560
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns the maximum cDNA location of the variant that can be used for protein annotation |
1561
|
|
|
|
|
1562
|
|
|
|
=item Returns : |
1563
|
|
|
|
|
1564
|
|
|
|
Integer - cDNA position |
1565
|
|
|
|
|
1566
|
|
|
|
=item Params : |
1567
|
|
|
|
|
1568
|
|
|
|
A L<Annotation|Sanger::CGP::Vagrent::Data::Annotation> representing the cDNA annotation |
1569
|
|
|
|
|
1570
|
|
|
|
=back |
1571
|
|
|
|
|
1572
|
|
|
|
=head3 _isStartGained |
1573
|
|
|
|
|
1574
|
|
|
|
=over |
1575
|
|
|
|
|
1576
|
|
|
|
=item Usage : |
1577
|
|
|
|
|
1578
|
|
|
|
if($annotator->_isStartGained($var,$tran,$mRNAmin,$mRNAmax,$wt,$mt)){ |
1579
|
|
|
|
....... |
1580
|
|
|
|
} |
1581
|
|
|
|
|
1582
|
|
|
|
=item Function : |
1583
|
|
|
|
|
1584
|
|
|
|
Abstract internal function, must be implemented in subclass. Returns returns true if there is a start codon created or moved in the 5' UTR |
1585
|
|
|
|
|
1586
|
|
|
|
=item Returns : |
1587
|
|
|
|
|
1588
|
|
|
|
Boolean |
1589
|
|
|
|
|
1590
|
|
|
|
=item Params : |
1591
|
|
|
|
|
1592
|
|
|
|
A Sanger::CGP::Vagrent::Data::AbstractVariation implementing object |
1593
|
|
|
|
A Sanger::CGP::Vagrent::Data::Transcript object |
1594
|
|
|
|
Integer - Minimum mRNA coordinate of the variant |
1595
|
|
|
|
Integer - Maximum mRNA coordinate of the variant |
1596
|
|
|
|
String - Wildtype variant sequence |
1597
|
|
|
|
String - Mutant variant sequence |
1598
|
|
|
|
|
1599
|
|
|
|
=back |