Genetic Variant VWA2:p.Arg69Met (chr10-114254993-G-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001272046.2(VWA2):c.206G>T(p.Arg69Met) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,613,194 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 5 hom. )

Consequence

VWA2
NM_001272046.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.69

Variant links:

Genes affected

VWA2 (HGNC:24709): (von Willebrand factor A domain containing 2) This gene encodes a member of the von Willebrand factor A-like domain protein superfamily. The encoded protein is localized to the extracellular matrix and may serve as a structural component in basement membranes or in anchoring structures on scaffolds of collagen VII or fibrillin. This gene has been linked to type 1A diabetes and is a candidate serological marker for colon cancer. [provided by RefSeq, Jan 2013]

VWA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022470683).

BP6

Variant 10-114254993-G-T is Benign according to our data. Variant chr10-114254993-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3050813.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA2	NM_001272046.2 link	c.206G>T	p.Arg69Met	missense_variant	Exon 4 of 14	ENST00000392982.8	NP_001258975.1	Q5GFL6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA2	ENST00000392982.8 link	c.206G>T	p.Arg69Met	missense_variant	Exon 4 of 14	1	NM_001272046.2	ENSP00000376708.3	Q5GFL6-1
VWA2	ENST00000603594.2 link	c.-656+1268G>T		intron_variant	Intron 3 of 10	2		ENSP00000473752.2	Q5GFL6-3
VWA2	ENST00000298715.8 link	n.456G>T		non_coding_transcript_exon_variant	Exon 4 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00547

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00207

AC:

519

AN:

250676

Hom.:

AF XY:

0.00203

AC XY:

276

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00656

Gnomad NFE exome

AF:

0.00273

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00228

AC:

3331

AN:

1460934

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

1633

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00641

Gnomad4 NFE exome

AF:

0.00248

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00214

AC:

326

AN:

152260

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00547

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00174

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00189

AC:

230

EpiCase

AF:

0.00322

EpiControl

AF:

0.00231

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VWA2-related disorder

Benign:1

Nov 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Benign

0.037

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.6

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.59

Sift

Benign

0.12

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.71

MVP

0.72

ClinPred

0.049

GERP RS

5.2

Varity_R

0.43

gMVP

0.74

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