Variant 1-1437118-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000476993.2(VWA1):c.265G>T(p.Gly89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

VWA1
ENST00000476993.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.825

Variant links:

Genes affected

VWA1 (HGNC:30910): (von Willebrand factor A domain containing 1) VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

VWA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA1	NM_022834.5 linkuse as main transcript	c.265G>T	p.Gly89Cys	missense_variant	2/3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 linkuse as main transcript	c.74-204G>T		intron_variant			NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 linkuse as main transcript	c.265G>T	p.Gly89Cys	missense_variant	2/3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000495558.1 linkuse as main transcript	c.160G>T	p.Gly54Cys	missense_variant	2/2	2		ENSP00000463643.1	J3QLP3
VWA1	ENST00000471398.1 linkuse as main transcript	c.385G>T	p.Gly129Cys	missense_variant	2/2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 linkuse as main transcript	c.74-204G>T		intron_variant		2		ENSP00000423404.1	Q6PCB0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453470

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721728

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 01, 2022

The c.265G>T (p.G89C) alteration is located in exon 2 (coding exon 2) of the VWA1 gene. This alteration results from a G to T substitution at nucleotide position 265, causing the glycine (G) at amino acid position 89 to be replaced by a cysteine (C). 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

0.23

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Uncertain

0.79

.;D;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

T;T;T

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.1

.;M;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.8

.;D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.015

.;D;.

Sift4G

Uncertain

0.024

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.30

MutPred

0.62

.;Loss of disorder (P = 0.0124);.;

MVP

0.81

MPC

0.25

ClinPred

0.97

GERP RS

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.56

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

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