rs113452150

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000093.5(COL5A1):c.4906G>A(p.Ala1636Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 9.86

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:

LOC101448202 (HGNC:):

LOC101448202 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL5A1

BP4

Computational evidence support a benign effect (MetaRNN=0.18039548).

BP6

Variant 9-134824807-G-A is Benign according to our data. Variant chr9-134824807-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213062.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=4}.

BS2

High AC in GnomAd at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.4906G>A	p.Ala1636Thr	missense_variant	62/66	ENST00000371817.8
LOC101448202	NR_103451.2 linkuse as main transcript	n.71-4598C>T		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1 linkuse as main transcript	c.4906G>A	p.Ala1636Thr	missense_variant	62/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.4906G>A	p.Ala1636Thr	missense_variant	62/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4906G>A	p.Ala1636Thr	missense_variant	62/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4906G>A	p.Ala1636Thr	missense_variant	62/66	2		A2	P20908-2
COL5A1	ENST00000460264.5 linkuse as main transcript	n.374G>A		non_coding_transcript_exon_variant	3/5	3
COL5A1	ENST00000465877.1 linkuse as main transcript	n.86G>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000234

AC:

AN:

248380

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

134712

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00317

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000710

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000827

AC:

126

AN:

152312

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00281

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000774

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2022	BS1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2020	This variant is associated with the following publications: (PMID: 29924831) -

Ehlers-Danlos syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 10, 2022

- -

COL5A1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 31, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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, classic type, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.050

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.0

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.023

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;.

Vest4

0.86

MVP

0.84

MPC

0.29

ClinPred

0.23

GERP RS

4.2

Varity_R

0.72

gMVP

0.85

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