rs138579182

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000093.5(COL5A1):c.574G>A(p.Asp192Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,818 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 41 hom., cov: 33)

Exomes 𝑓: 0.020 ( 378 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 2.18

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=0.0070186555).

BP6

Variant 9-134701253-G-A is Benign according to our data. Variant chr9-134701253-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134701253-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2362/152148) while in subpopulation NFE AF= 0.0223 (1519/68002). AF 95% confidence interval is 0.0214. There are 41 homozygotes in gnomad4. There are 1222 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2362 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.574G>A	p.Asp192Asn	missense_variant	Exon 4 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.574G>A	p.Asp192Asn	missense_variant	Exon 4 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.574G>A	p.Asp192Asn	missense_variant	Exon 4 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL5A1	ENST00000371817.8 link	c.574G>A	p.Asp192Asn	missense_variant	Exon 4 of 66	1	NM_000093.5	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4 link	c.574G>A	p.Asp192Asn	missense_variant	Exon 4 of 66	2		ENSP00000360885.4	P20908-2H7BY82
COL5A1	ENST00000464187.1 link	n.996G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2361

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00685

Gnomad FIN

AF:

0.0479

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0167

AC:

4170

AN:

250328

Hom.:

AF XY:

0.0167

AC XY:

2263

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00229

Gnomad AMR exome

AF:

0.00440

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00712

Gnomad FIN exome

AF:

0.0493

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0198

AC:

28903

AN:

1461670

Hom.:

378

Cov.:

AF XY:

0.0195

AC XY:

14172

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.0177

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00748

Gnomad4 FIN exome

AF:

0.0470

Gnomad4 NFE exome

AF:

0.0215

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0155

AC:

2362

AN:

152148

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1222

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00306

Gnomad4 AMR

AF:

0.00569

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00706

Gnomad4 FIN

AF:

0.0479

Gnomad4 NFE

AF:

0.0223

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0189

Hom.:

Bravo

AF:

0.0115

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0206

AC:

177

ExAC

AF:

0.0167

AC:

2022

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0172

EpiControl

AF:

0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2013

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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

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.574G>A (p.Asp192Asn) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2009/119100 control chromosomes (28 homozygotes) at a frequency of 0.0168682, which is approximately 13495 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. To our knowledge, the variant of interest has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 06, 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

Benign:2

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

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone, for Ehlers-Danlos syndrome, classic type, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BP5 => Variant found in a case with an alternate molecular basis for disease. BA1 => Allele frequency is >1% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. Allele frequency is >4% in European (Finnish). -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Mar 15, 2022

Genome-Nilou Lab

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

- -

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

Feb 05, 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 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.58

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.70

N;.

REVEL

Benign

0.057

Sift

Benign

0.55

T;.

Sift4G

Benign

0.49

T;T

Polyphen

0.031

B;.

Vest4

0.072

MPC

0.21

ClinPred

0.0087

GERP RS

3.2

Varity_R

0.036

gMVP

0.22

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