Report NA12878

Technical Report for Bioinformatic Analysis

Sample: NA12878_03 (ex1)

sample sex: female
Processing system: HaloPlex HSP v2
Processing system type: Panel Haloplex
Sequencer: MiSeq
Date of the sequencing run: 18.03.2025
Read length: 158+8+158
Reference genome: GRCh37
Date: 19.02.2021
Analysis pipeline: megSAP 0.2-486-gc928f885
Analysis software: cppNGSD-TEST

Phenotype information

Target region
The target region includes CCDS ("consensus coding sequence") of the genes listed below ±20 flanking bases of the intronic sequence. It may comprise additional exons and/or flanking bases.
Name: panel
Genes analyzed: 3 (see coverage statistics)

Criteria for variant filtering
- Allele frequency ≤ 1.00%

Small variants in target region: 135
SNVs/InDels selected for report: 2
CNVs/SVs/REs selected for report: 6

If present, the following tables contain: likely pathogenic variants (class 4)^* and pathogenic variants (class 5)^*, for which a contribution to the clinical symptoms of the patient is conceivable, and variants of uncertain significance (class 3)^*, for which a further evaluation of the clinical relevance by follow-up examinations may be useful. Depending on the type of genetic alteration, family history and clinical features of the patient further investigations might change the classification of variants.
A (uncommented) list of all detected variants can be provided on request.
In case of a suspected clinical diagnosis genetic counseling is necessary to evaluate the indication/possibility of further genetic studies.
^* For information on the classification of variants, see the general information.

List of prioritized small variants

Variant	Genotype	Genes	Details	Class	Inheritance	gnomAD allele frequency (control cohort)	RNA
chr13:40793233 T > A	hom (comp-het)	SLC25A15	SLC25A15:ENST00000338625.1/NM_014252:c.7T>A:p.Ser3Thr	3	n/a	n/a	splicing effect validated by RNA dataset
OMIM ID: 603861 Details: GENE=SLC25A15 PHENOS=Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome,238970,Autosomal recessive
chr16:89531961 G > A	het (de-novo) (mosaic)	SPG7	SPG7:ENST00000268704.1:c.1045G>A:p.Gly349Ser	5	n/a	0.080%	n/a
OMIM ID: 602783 Details: GENE=SPG7 PHENOS=Spastic paraplegia 7,autosomal recessive,607259,Autosomal recessive,Autosomal dominant

List of prioritized copy-number variants and/or structural variants

CNV/SV/RE	Position	Size	copy-number/genotype	Genes	Class	Inheritance	RNA
deletion	chr21:10541092-10649856	108.765 kb / 22 regions	1 (comp-het)	IGHV1OR21-1, TPTE	n/a	n/a	no splicing effect found in RNA dataset
deletion	chr21:26799369-26991734	192.366 kb / 13 regions	0 (comp-het)		n/a	n/a	no splicing effect found in RNA dataset
insertion	chr1:934143-934144		hom	HES4	n/a	n/a	RNA dataset not usable
translocation	chr1:1584540-1584550 <-> chr19:2301860-2301870		hom		n/a	n/a	n/a
deletion	chr1:1598413-1598580	0.168 kb	hom	SLC35E2B	n/a	n/a	n/a
repeat expansion	chr1:57367043-57367118		expanded	DAB1		n/a

variant type	regions	Genes	Inheritance	comment
uncalled CNV	chr2:123456-789012	EPRS	AR	This is a comment! And it has multiple lines!

Classification of variants:
Classification and interpretation of variants: The classification of variants is based on the criteria of Plon et al. (PMID: 18951446). A short description of each class can be found in the following
Class 5, pathogenic variant: The variant is considered to be the cause of the patient's disease.
Class 4, probably pathogenic variants: The identified variant is considered to be the probable cause of the patient's disease. This information should be used cautiously for clinical decision-making, as there is still a degree of uncertainty.
Class 3, variant of unclear significance (VUS): The variant has characteristics of being an independent disease-causing mutation, but insufficient or conflicting evidence exists.
Class 2, most likely benign variants: The variant is not likely to be the cause of the tested disease. Class 2 variants are not reported, but can be provided upon request.
Class 1, benign variants: The variant is not considered to be the cause of the tested disease. Class 1 variants are not reported, but can be provided upon request.

Coverage statistics of target region
Average sequencing depth: 125.47
Average sequencing depth (chrMT): 0.00

Gap report based on entire target region
Bases: 271536
Percentage of regions with depth <20: 15449
Percentage gaps: 5.69%
Genes without gaps:
Genes with incomplete coverage (missing bp in brackets): CYP7B1 (243), SLC25A15 (129), SPG7 (126)

Details regions with depth <20:

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	243	chr8	64615713-64615740, 64616216-64616218, 64624393-64624515, 64798456-64798544
SLC25A15	129	chr13	40799186-40799314
SPG7	126	chr16	89524046-89524104, 89554476-89554542
no gene overlap	14951	-	-

Gaps closed by Sanger sequencing:

Gene	Bases	Chromosome	Coordinates (hg38)
SPG7	59	chr16	89524046-89524104

Base sum:59

Gaps checked by visual inspection of raw data:

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	28	chr8	64615713-64615740
CYP7B1	3	chr8	64616216-64616218

Base sum:31

gaps remaining

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	212	chr8	64624393-64624515, 64798456-64798544
SLC25A15	129	chr13	40799186-40799314
SPG7	67	chr16	89554476-89554542
no gene overlap	14951	-	-

Percentage of regions with depth <20 after closing gaps: 15359
Percentage gaps after closing gaps: 5.66%

Gap report based on exons of target region ± 20 Bases
Bases: 5975
Percentage of regions with depth <20: 528
Percentage gaps: 8.84%
Genes without gaps:
Genes with incomplete coverage (missing bp in brackets): CYP7B1 (263), SLC25A15 (129), SPG7 (136)

Details regions with depth <20:

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	263	chr8	64615713-64615740, 64616216-64616218, 64624383-64624515, 64798446-64798544
SLC25A15	129	chr13	40799186-40799314
SPG7	136	chr16	89524046-89524104, 89554466-89554542

Gaps closed by Sanger sequencing:

Gene	Bases	Chromosome	Coordinates (hg38)
SPG7	59	chr16	89524046-89524104

Base sum:59

Gaps checked by visual inspection of raw data:

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	28	chr8	64615713-64615740
CYP7B1	3	chr8	64616216-64616218

Base sum:31

gaps remaining

Gene	Bases	Chromosome	Coordinates (hg38)
CYP7B1	232	chr8	64624383-64624515, 64798446-64798544
SLC25A15	129	chr13	40799186-40799314
SPG7	77	chr16	89554466-89554542

Percentage of regions with depth <20 after closing gaps: 438
Percentage gaps after closing gaps: 7.33%

Coverage statistics of RNA sample
Number of reads: 10.99 Mio
Average sequencing depth: 15.85
Average sequencing depth of housekeeping genes: 263.87
Covered genes: 136985

OMIM gene and phenotypes

Gene	HGNC ID	gene MIM	phenotype MIM	phenotype	preferred phenotype
CYP7B1	HGNC:2652	603711	270800	Spastic paraplegia 5A, autosomal recessive, 270800 (3)	yes
SLC25A15	HGNC:10985	603861	238970	Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 (3)	no
SPG7	HGNC:11237	602783	607259	Spastic paraplegia 7, autosomal recessive, 607259 (3)	no

Polygenic Risk Scores (PRS)

Trait	PRS	Publication	Score	z-score	population (estimated from NGS)
Breast Cancer	PGS000004	Mavaddat N et al. Am J Hum Genet (2018). doi:10.1016/j.ajhg.2018.11.002	-0.2773	0.240	European

A validated risk estimation program must be used to judge the clinical importance of a PRS, e.g. CanRisk.org for breast cancer. The ethnicity of the patient must also be considered.