rs142313124

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.2096C>T(p.Thr699Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T699T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 3.00

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 (MetaRNN=0.15634358).

BP6

Variant 9-134766461-C-T is Benign according to our data. Variant chr9-134766461-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000597 (91/152316) while in subpopulation NFE AF= 0.000985 (67/68030). AF 95% confidence interval is 0.000795. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.2096C>T	p.Thr699Met	missense_variant	Exon 22 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.2096C>T	p.Thr699Met	missense_variant	Exon 22 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.2096C>T	p.Thr699Met	missense_variant	Exon 22 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.2096C>T	p.Thr699Met	missense_variant	Exon 22 of 66	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820.4 link	c.2096C>T	p.Thr699Met	missense_variant	Exon 22 of 66	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000634

AC:

159

AN:

250916

Hom.:

AF XY:

0.000714

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000944

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00112

AC:

1630

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

780

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000597

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000793

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000601

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29924831) -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL5A1: BS1 -

Dec 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Aug 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL5A1 c.2096C>T (p.Thr699Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 250916 control chromosomes, predominantly at a frequency of 0.00094 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2096C>T has been reported in the literature in individuals affected with keratoconus, however without strong evidence for causality (e.g., lack of co-occurrence and co-segregation data), and the variant was also identified in healthy controls (e.g., Lucas_2018, Fransen_2021). These reports therefore do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33737726, 29924831). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; seven submitters classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

May 22, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type

Benign:1Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 12/06/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

COL5A1-related disorder

Benign:1

Oct 27, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Sep 21, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.16

T;T

MetaSVM

Uncertain

0.065

MutationAssessor

Benign

0.99

L;L

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.6

N;.

REVEL

Uncertain

0.34

Sift

Benign

0.071

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.82

P;.

Vest4

0.40

MVP

0.78

MPC

1.5

ClinPred

0.025

GERP RS

3.8

Varity_R

0.041

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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