10-114278022-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001272046.2(VWA2):c.675G>A(p.Ser225=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,612,462 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (3 hom.)
• Consequence: VWA2 NM_001272046.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.26

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-114278022-G-A is Benign according to our data. Variant chr10-114278022-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 774563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA2	NM_001272046.2	c.675G>A	p.Ser225=	synonymous_variant	7/14	ENST00000392982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA2	ENST00000392982.8	c.675G>A	p.Ser225=	synonymous_variant	7/14	1	NM_001272046.2	P1
VWA2	ENST00000603594.2	c.-242G>A		5_prime_UTR_variant	6/11	2
VWA2	ENST00000298715.8	n.925G>A		non_coding_transcript_exon_variant	7/12	2

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000923 AC: 231 AN: 250182 Hom.: 2 AF XY: 0.000975 AC XY: 132 AN XY: 135366

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000762

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000738 AC: 1078 AN: 1460130 Hom.: 3 Cov.: 31 AF XY: 0.000737 AC XY: 535 AN XY: 726102

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000652

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74500

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000671 Hom.: 0

Bravo AF: 0.00101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

VWA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2020

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.57
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142441906; hg19: chr10-116037781;