9-134700009-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.378G>T(p.Gln126His) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,613,802 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 18 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.19

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012970805).

BP6

Variant 9-134700009-G-T is Benign according to our data. Variant chr9-134700009-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 136918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134700009-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00234 (357/152360) while in subpopulation EAS AF= 0.0324 (168/5178). AF 95% confidence interval is 0.0284. There are 4 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.378G>T	p.Gln126His	missense_variant	Exon 3 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.378G>T	p.Gln126His	missense_variant	Exon 3 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.378G>T	p.Gln126His	missense_variant	Exon 3 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL5A1	ENST00000371817.8 link	c.378G>T	p.Gln126His	missense_variant	Exon 3 of 66	1	NM_000093.5	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4 link	c.378G>T	p.Gln126His	missense_variant	Exon 3 of 66	2		ENSP00000360885.4	P20908-2H7BY82
COL5A1	ENST00000464187.1 link	n.800G>T		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0326

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00367

AC:

923

AN:

251178

Hom.:

AF XY:

0.00356

AC XY:

483

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.0320

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00787

Gnomad NFE exome

AF:

0.000969

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00164

AC:

2399

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1217

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.0342

Gnomad4 SAS exome

AF:

0.000777

Gnomad4 FIN exome

AF:

0.00723

Gnomad4 NFE exome

AF:

0.000383

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00234

AC:

357

AN:

152360

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

223

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.0324

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00369

AC:

448

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Oct 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Dec 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL5A1: BS1, BS2 -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Dec 20, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Oct 19, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;.

Vest4

0.83

MutPred

0.43

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.82

MPC

0.62

ClinPred

0.10

GERP RS

2.9

Varity_R

0.46

gMVP

0.55

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