Variant 1-1436947-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The ENST00000476993.2(VWA1):c.94C>T(p.Arg32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,607,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

VWA1
ENST00000476993.2 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 1.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1436947-C-T is Pathogenic according to our data. Variant chr1-1436947-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 830326.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA1	NM_022834.5 linkuse as main transcript	c.94C>T	p.Arg32*	stop_gained	2/3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 linkuse as main transcript	c.74-375C>T		intron_variant			NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA1	ENST00000476993.2 linkuse as main transcript	c.94C>T	p.Arg32*	stop_gained	2/3	1	NM_022834.5	ENSP00000417185.1		Q6PCB0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000409

AC:

AN:

244670

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133032

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.0000662

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1455278

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

723194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuromuscular disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Jan 01, 2020

- -

Neuronopathy, distal hereditary motor, autosomal recessive 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 17, 2023

- -

VWA1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2023

The VWA1 c.94C>T variant is predicted to result in premature protein termination (p.Arg32*). This variant has been reported in the compound heterozygous state in an individual with neuromyopathy (Table 1, Deschauer et al. 2021. PubMed ID: 33459760). This variant is reported in 0.019% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-1372327-C-T). Nonsense variants in VWA1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.072

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.10

MutationTaster

Benign

1.0

A;N;N

Vest4

0.035

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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