10-114278756-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001272046.2(VWA2):c.738G>A(p.Thr246=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: VWA2 NM_001272046.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -15 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 criteria_provided_single_submitter, 1 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 GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA2	NM_001272046.2	c.738G>A	p.Thr246=	synonymous_variant	8/14	ENST00000392982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA2	ENST00000392982.8	c.738G>A	p.Thr246=	synonymous_variant	8/14	1	NM_001272046.2	P1
VWA2	ENST00000603594.2	c.-179G>A		5_prime_UTR_variant	7/11	2
VWA2	ENST00000298715.8	n.988G>A		non_coding_transcript_exon_variant	8/12	2

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1379 AN: 152210 Hom.: 13 Cov.: 32

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.: 15 AF XY: 0.00988 AC XY: 1342 AN XY: 135802

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.: 32 AF XY: 0.0129 AC XY: 9375 AN XY: 727088

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.: 13 Cov.: 32 AF XY: 0.00888 AC XY: 661 AN XY: 74470

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.: 4

Bravo AF: 0.00750

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

VWA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2022

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

Other links and lift over

dbSNP: rs141503948; hg19: chr10-116038515;