Variant 16-22116859-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173615.5(VWA3A):c.916A>T(p.Met306Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,612,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

VWA3A
NM_173615.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.443

Variant links:

Genes affected

VWA3A (HGNC:27088): (von Willebrand factor A domain containing 3A) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWA3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03316188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA3A	NM_173615.5 linkuse as main transcript	c.916A>T	p.Met306Leu	missense_variant	10/34	ENST00000389398.10	NP_775886.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA3A	ENST00000389398.10 linkuse as main transcript	c.916A>T	p.Met306Leu	missense_variant	10/34	5	NM_173615.5	ENSP00000374049	P1	A6NCI4-1
VWA3A	ENST00000568328.5 linkuse as main transcript	c.916A>T	p.Met306Leu	missense_variant	10/23	1		ENSP00000457770
VWA3A	ENST00000566668.1 linkuse as main transcript	n.1110A>T		non_coding_transcript_exon_variant	9/20	2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000725

AC:

AN:

248386

Hom.:

AF XY:

0.0000667

AC XY:

AN XY:

134878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1460408

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000711

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000164

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.916A>T (p.M306L) alteration is located in exon 10 (coding exon 10) of the VWA3A gene. This alteration results from a A to T substitution at nucleotide position 916, causing the methionine (M) at amino acid position 306 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.3

DANN

Benign

0.39

DEOGEN2

Benign

0.0012

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.43

.;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.49

.;N

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.033

Sift

Benign

0.43

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.0

.;B

Vest4

0.15

MutPred

0.43

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.014

MPC

0.041

ClinPred

0.036

GERP RS

-2.6

Varity_R

0.070

gMVP

0.18

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