rs139468527

Positions:

chr9-134690995-C-T

Variant summary

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

The NM_000093.5(COL5A1):c.193C>T(p.Arg65Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,613,832 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 12 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.26

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=0.06795913).

BP6

Variant 9-134690995-C-T is Benign according to our data. Variant chr9-134690995-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134690995-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00141 (215/152388) while in subpopulation SAS AF= 0.00538 (26/4834). AF 95% confidence interval is 0.00377. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.193C>T	p.Arg65Trp	missense_variant	2/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 linkuse as main transcript	c.193C>T	p.Arg65Trp	missense_variant	2/66		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.193C>T	p.Arg65Trp	missense_variant	2/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.193C>T	p.Arg65Trp	missense_variant	2/66	1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.193C>T	p.Arg65Trp	missense_variant	2/66	2		ENSP00000360885	A2	P20908-2
COL5A1	ENST00000464187.1 linkuse as main transcript	n.379C>T		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00537

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00216

AC:

543

AN:

251154

Hom.:

AF XY:

0.00248

AC XY:

337

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00775

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00591

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00166

AC:

2419

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1372

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00826

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00621

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.00126

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152388

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00194

AC:

236

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	COL5A1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	This variant is associated with the following publications: (PMID: 24036952, 28748566, 30858776, 31903434) -

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 21, 2023

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2017

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2021

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.54

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.068

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.3

M;M

MutationTaster

Benign

0.63

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.88

MVP

0.65

MPC

0.66

ClinPred

0.11

GERP RS

1.3

Varity_R

0.44

gMVP

0.67

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