rs61735045

Variant names:

• chr9-134750808-G-A
• rs61735045
• NM_000093.5:c.1588G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134750808-G-A
• chr9-134750808-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 7.24
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 38863.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 = 0.0317 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4824 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4827 AN: 152178 Hom.: 111 Cov.: 33

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

GnomAD2 exomes AF: 0.0347 AC: 8689 AN: 250360 AF XY: 0.0365

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 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.: 33 AF XY: 0.0419 AC XY: 30477 AN XY: 726732

African (AFR) AF: 0.00636 AC: 213 AN: 33480

American (AMR) AF: 0.0248 AC: 1107 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 765 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39698

South Asian (SAS) AF: 0.0378 AC: 3262 AN: 86252

European-Finnish (FIN) AF: 0.0331 AC: 1741 AN: 52544

Middle Eastern (MID) AF: 0.0394 AC: 227 AN: 5768

European-Non Finnish (NFE) AF: 0.0461 AC: 51291 AN: 1111856

Other (OTH) AF: 0.0394 AC: 2381 AN: 60384

GnomAD4 genome AF: 0.0317 AC: 4824 AN: 152296 Hom.: 111 Cov.: 33 AF XY: 0.0301 AC XY: 2243 AN XY: 74464

African (AFR) AF: 0.00767 AC: 319 AN: 41576

American (AMR) AF: 0.0312 AC: 478 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5162

South Asian (SAS) AF: 0.0387 AC: 187 AN: 4830

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10616

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3242 AN: 68020

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0402 Hom.: 253

Bravo AF: 0.0301

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0433 AC: 372

ExAC AF: 0.0353 AC: 4291

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0515

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Oct 31, 2012

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.

Sep 07, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: 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

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 10, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome, classic type, 1 Benign:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome, classic type Benign:1 Other:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

May 21, 2015

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

Jun 17, 2022

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

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Connective tissue disorder Benign:1

Nov 01, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.88	L
PhyloP100		7.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.23
MPC		1.5
ClinPred		0.031	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.90
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs61735045; hg19: chr9-137642654; COSMIC: COSV65667766;