chr9-134817038-C-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.4135C>T(p.Pro1379Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00768 in 1,613,868 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 9 hom., cov: 34)

Exomes 𝑓: 0.0079 ( 72 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 4.85

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=0.012166917).

BP6

Variant 9-134817038-C-T is Benign according to our data. Variant chr9-134817038-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134817038-C-T is described in Lovd as [Benign]. Variant chr9-134817038-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00603 (919/152342) while in subpopulation NFE AF= 0.00883 (601/68036). AF 95% confidence interval is 0.00825. There are 9 homozygotes in gnomad4. There are 431 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 919 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.4135C>T	p.Pro1379Ser	missense_variant	Exon 53 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.4135C>T	p.Pro1379Ser	missense_variant	Exon 53 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.4135C>T	p.Pro1379Ser	missense_variant	Exon 53 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.4135C>T	p.Pro1379Ser	missense_variant	Exon 53 of 66	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820.4 link	c.4135C>T	p.Pro1379Ser	missense_variant	Exon 53 of 66	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.00605

AC:

921

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00885

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.00749

AC:

1882

AN:

251426

Hom.:

AF XY:

0.00787

AC XY:

1070

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00758

Gnomad FIN exome

AF:

0.00674

Gnomad NFE exome

AF:

0.00885

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00785

AC:

11478

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

5816

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00496

Gnomad4 ASJ exome

AF:

0.0245

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00752

Gnomad4 FIN exome

AF:

0.00624

Gnomad4 NFE exome

AF:

0.00805

Gnomad4 OTH exome

AF:

0.00788

GnomAD4 genome

AF:

0.00603

AC:

919

AN:

152342

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

431

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00621

Gnomad4 FIN

AF:

0.00687

Gnomad4 NFE

AF:

0.00883

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00877

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00741

AC:

900

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0116

EpiControl

AF:

0.00990

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Aug 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL5A1: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.4135C>T (p.Pro1379Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/5 in silico tools predict a damaging outcome for this variant, however these predictions have yet to be confirmed by functional studies. This variant was found in 900/121304 control chromosomes (7 homozygotes) at a frequency of 0.0074194, which is approximately 5935 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. Taken together, this variant is classified as benign. -

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

Mar 02, 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

Benign:1

May 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal

Benign:1

Oct 04, 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;.

Vest4

0.58

MVP

0.86

MPC

0.30

ClinPred

0.013

GERP RS

5.0

Varity_R

0.38

gMVP

0.29

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