rs3827848

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000093.5(COL5A1):c.4122G>A(p.Thr1374=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,610 control chromosomes in the GnomAD database, including 19,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1608 hom., cov: 33)

Exomes 𝑓: 0.15 ( 17670 hom. )

Consequence

COL5A1
NM_000093.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9565

Clinical Significance

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

Conservation

PhyloP100: 1.23

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 9-134815988-G-A is Benign according to our data. Variant chr9-134815988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134815988-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.4122G>A	p.Thr1374=	splice_region_variant, synonymous_variant	52/66	ENST00000371817.8
COL5A1	NM_001278074.1 linkuse as main transcript	c.4122G>A	p.Thr1374=	splice_region_variant, synonymous_variant	52/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.4122G>A	p.Thr1374=	splice_region_variant, synonymous_variant	52/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4122G>A	p.Thr1374=	splice_region_variant, synonymous_variant	52/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4122G>A	p.Thr1374=	splice_region_variant, synonymous_variant	52/66	2		A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21362

AN:

152044

Hom.:

1606

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.133

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.147

AC:

36952

AN:

251360

Hom.:

2888

AF XY:

0.147

AC XY:

19954

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.172

Gnomad SAS exome

AF:

0.142

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.153

AC:

223574

AN:

1461448

Hom.:

17670

Cov.:

AF XY:

0.153

AC XY:

111168

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.150

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.184

Gnomad4 NFE exome

AF:

0.158

Gnomad4 OTH exome

AF:

0.150

GnomAD4 genome

AF:

0.141

AC:

21386

AN:

152162

Hom.:

1608

Cov.:

AF XY:

0.139

AC XY:

10307

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.110

Gnomad4 ASJ

AF:

0.110

Gnomad4 EAS

AF:

0.163

Gnomad4 SAS

AF:

0.134

Gnomad4 FIN

AF:

0.182

Gnomad4 NFE

AF:

0.161

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.153

Hom.:

4447

Bravo

AF:

0.132

Asia WGS

AF:

0.144

AC:

503

AN:

3478

EpiCase

AF:

0.152

EpiControl

AF:

0.150

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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.4122G>A (p.Thr1374Thr) variant causes a missense change involving 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 weakening the canonical donor cite. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17922/121286 control chromosomes (1465 homozygotes) at a frequency of 0.1477664, which is approximately 118213 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. Taken together, this variant is classified as benign. -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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 04, 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 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

-0.31

Cadd

Benign

Dann

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.96

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: 0

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