Genetic Variant VWA2:p.Thr246Thr (chr10-114278756-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001272046.2(VWA2):c.738G>A(p.Thr246Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,920 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0090 ( 13 hom., cov: 32)

Exomes 𝑓: 0.013 ( 157 hom. )

Consequence

VWA2
NM_001272046.2 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.49

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 10-114278756-G-A is Benign according to our data. Variant chr10-114278756-G-A is described in ClinVar as [Benign]. Clinvar id is 3042390.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0133 (19388/1461592) while in subpopulation NFE AF= 0.0157 (17416/1112010). AF 95% confidence interval is 0.0155. There are 157 homozygotes in gnomad4_exome. There are 9375 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA2	NM_001272046.2 link	c.738G>A	p.Thr246Thr	synonymous_variant	Exon 8 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.738G>A	p.Thr246Thr	synonymous_variant	Exon 8 of 14	1	NM_001272046.2	ENSP00000376708.3	Q5GFL6-1
VWA2	ENST00000603594 link	c.-179G>A		5_prime_UTR_variant	Exon 7 of 11	2		ENSP00000473752.2	Q5GFL6-3
VWA2	ENST00000298715.8 link	n.988G>A		non_coding_transcript_exon_variant	Exon 8 of 12	2

Frequencies

GnomAD3 genomes

AF:

0.00906

AC:

1379

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00260

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00962

AC:

2416

AN:

251180

Hom.:

AF XY:

0.00988

AC XY:

1342

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00203

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.0133

AC:

19388

AN:

1461592

Hom.:

157

Cov.:

AF XY:

0.0129

AC XY:

9375

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00215

Gnomad4 FIN exome

AF:

0.0189

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.00932

GnomAD4 genome

AF:

0.00904

AC:

1377

AN:

152328

Hom.:

Cov.:

AF XY:

0.00888

AC XY:

661

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00260

Gnomad4 AMR

AF:

0.00202

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.00750

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VWA2-related disorder

Benign:1

Oct 13, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.33

DANN

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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