9-134796895-C-T

Position:

chr9-134796895-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000093.5(COL5A1):c.2892C>T(p.Gly964=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,330 control chromosomes in the GnomAD database, including 1,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 112 hom., cov: 34)

Exomes 𝑓: 0.040 ( 1334 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0890

Variant links:

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]

COL5A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 9-134796895-C-T is Benign according to our data. Variant chr9-134796895-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134796895-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.089 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.2892C>T	p.Gly964=	synonymous_variant	36/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 linkuse as main transcript	c.2892C>T	p.Gly964=	synonymous_variant	36/66		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.2892C>T	p.Gly964=	synonymous_variant	36/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.2892C>T	p.Gly964=	synonymous_variant	36/66	1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.2892C>T	p.Gly964=	synonymous_variant	36/66	2		ENSP00000360885	A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5145

AN:

152048

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0272

Gnomad ASJ

AF:

0.0400

Gnomad EAS

AF:

0.0363

Gnomad SAS

AF:

0.0884

Gnomad FIN

AF:

0.0416

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0377

GnomAD3 exomes

AF:

0.0409

AC:

10262

AN:

250924

Hom.:

245

AF XY:

0.0440

AC XY:

5967

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.0206

Gnomad ASJ exome

AF:

0.0423

Gnomad EAS exome

AF:

0.0356

Gnomad SAS exome

AF:

0.0795

Gnomad FIN exome

AF:

0.0430

Gnomad NFE exome

AF:

0.0403

Gnomad OTH exome

AF:

0.0399

GnomAD4 exome

AF:

0.0401

AC:

58569

AN:

1461164

Hom.:

1334

Cov.:

AF XY:

0.0412

AC XY:

29948

AN XY:

726928

show subpopulations

Gnomad4 AFR exome

AF:

0.0187

Gnomad4 AMR exome

AF:

0.0209

Gnomad4 ASJ exome

AF:

0.0429

Gnomad4 EAS exome

AF:

0.0513

Gnomad4 SAS exome

AF:

0.0769

Gnomad4 FIN exome

AF:

0.0406

Gnomad4 NFE exome

AF:

0.0381

Gnomad4 OTH exome

AF:

0.0410

GnomAD4 genome

AF:

0.0339

AC:

5155

AN:

152166

Hom.:

112

Cov.:

AF XY:

0.0349

AC XY:

2594

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0181

Gnomad4 AMR

AF:

0.0272

Gnomad4 ASJ

AF:

0.0400

Gnomad4 EAS

AF:

0.0364

Gnomad4 SAS

AF:

0.0885

Gnomad4 FIN

AF:

0.0416

Gnomad4 NFE

AF:

0.0385

Gnomad4 OTH

AF:

0.0406

Alfa

AF:

0.0293

Hom.:

Bravo

AF:

0.0308

Asia WGS

AF:

0.0780

AC:

269

AN:

3478

EpiCase

AF:

0.0418

EpiControl

AF:

0.0422

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 10, 2017	Variant summary: The COL5A1 c.2892C>T (p.Gly964Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not significantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. The variant does not fall within a known functional domain of the protein (InterPro). This variant was found in 5033/120846 control chromosomes (133 homozygotes) at a frequency of 0.041648, which is approximately 33318 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable clinical diagnostic laboratories/databases, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2012	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. -

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, 2015

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

Jul 16, 2022

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.7

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over