9-134750808-G-A

Position:

chr9-134750808-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.1588G>A(p.Gly530Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,613,134 control chromosomes in the GnomAD database, including 1,546 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. G530G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 111 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1435 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 7.24

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.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056170523).

BP6

Variant 9-134750808-G-A is Benign according to our data. Variant chr9-134750808-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 38863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134750808-G-A is described in Lovd as [Likely_benign]. Variant chr9-134750808-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0317 (4824/152296) while in subpopulation NFE AF= 0.0477 (3242/68020). AF 95% confidence interval is 0.0463. There are 111 homozygotes in gnomad4. There are 2243 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4824 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.1588G>A	p.Gly530Ser	missense_variant	13/66	ENST00000371817.8
COL5A1	NM_001278074.1 linkuse as main transcript	c.1588G>A	p.Gly530Ser	missense_variant	13/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.1588G>A	p.Gly530Ser	missense_variant	13/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.1588G>A	p.Gly530Ser	missense_variant	13/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.1588G>A	p.Gly530Ser	missense_variant	13/66	2		A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4827

AN:

152178

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00770

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0313

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0385

Gnomad FIN

AF:

0.0325

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0476

Gnomad OTH

AF:

0.0411

GnomAD3 exomes

AF:

0.0347

AC:

8689

AN:

250360

Hom.:

208

AF XY:

0.0365

AC XY:

4953

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.00744

Gnomad AMR exome

AF:

0.0231

Gnomad ASJ exome

AF:

0.0282

Gnomad EAS exome

AF:

0.000762

Gnomad SAS exome

AF:

0.0395

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.0469

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0418

AC:

61014

AN:

1460838

Hom.:

1435

Cov.:

AF XY:

0.0419

AC XY:

30477

AN XY:

726732

show subpopulations

Gnomad4 AFR exome

AF:

0.00636

Gnomad4 AMR exome

AF:

0.0248

Gnomad4 ASJ exome

AF:

0.0293

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.0378

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0461

Gnomad4 OTH exome

AF:

0.0394

GnomAD4 genome

AF:

0.0317

AC:

4824

AN:

152296

Hom.:

111

Cov.:

AF XY:

0.0301

AC XY:

2243

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00767

Gnomad4 AMR

AF:

0.0312

Gnomad4 ASJ

AF:

0.0314

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0387

Gnomad4 FIN

AF:

0.0325

Gnomad4 NFE

AF:

0.0477

Gnomad4 OTH

AF:

0.0407

Alfa

AF:

0.0441

Hom.:

172

Bravo

AF:

0.0301

TwinsUK

AF:

0.0526

AC:

195

ALSPAC

AF:

0.0444

AC:

171

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0433

AC:

372

ExAC

AF:

0.0353

AC:

4291

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0492

EpiControl

AF:

0.0515

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Sep 07, 2017	BS1, BS2, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:4

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.1588G>A (p.Gly530Ser) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have yet to be confirmed by functional studies. This variant was found in 4263/119292 control chromosomes (103 homozygotes) at a frequency of 0.0357358, which is approximately 28589 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 In the past, this variant was considered disease-modifying in heterozygotes and disease-causing in homozygotes, but new data from ExAC is supporting the fact that it is a benign variant. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Ehlers-Danlos syndrome, classic type, 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jun 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Ehlers-Danlos syndrome, classic type

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

May 21, 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

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 17, 2022

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 01, 2021

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.094

T;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0056

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.88

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.3

N;.

REVEL

Uncertain

0.49

Sift

Benign

0.28

T;.

Sift4G

Benign

0.27

T;T

Polyphen

1.0

D;.

Vest4

0.23

MPC

1.5

ClinPred

0.031

GERP RS

4.5

Varity_R

0.10

gMVP

0.90

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