rs148648778

Positions:

• chr9-134782675-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.2439C>T​(p.Asp813Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000966 in 1,613,578 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (4 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.820

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 9-134782675-C-T is Benign according to our data. Variant chr9-134782675-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134782675-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00326 (496/152056) while in subpopulation AFR AF= 0.00948 (393/41456). AF 95% confidence interval is 0.00871. There are 5 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 496 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2439C>T	p.Asp813Asp	synonymous_variant	29/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2439C>T	p.Asp813Asp	synonymous_variant	29/66		NP_001265003.1
COL5A1	XM_017014266.3	c.2439C>T	p.Asp813Asp	synonymous_variant	29/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2439C>T	p.Asp813Asp	synonymous_variant	29/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2439C>T	p.Asp813Asp	synonymous_variant	29/66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 151940 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00134 AC: 337 AN: 251290 Hom.: 3 AF XY: 0.00107 AC XY: 145 AN XY: 135886

Gnomad AFR exome AF: 0.00985

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000727 AC: 1063 AN: 1461522 Hom.: 4 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 727036

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152056 Hom.: 5 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74332

Gnomad4 AFR AF: 0.00948

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00173 Hom.: 2

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	COL5A1: BP4, BP7, BS2 -

Ehlers-Danlos syndrome, classic type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2019	- -

Ehlers-Danlos syndrome, classic type, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.7
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148648778; hg19: chr9-137674521;