Variant 1-1435798-TGGCGCGGAGC-TGGCGCGGAGCGGCGCGGAGCGGCGCGGAGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_022834.5(VWA1):c.52_71dupGCGCGGAGCGGCGCGGAGCG(p.Gly25ArgfsTer18) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.5e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VWA1
NM_022834.5 frameshift, splice_region

Scores

Not classified

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.706

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1435798-T-TGGCGCGGAGCGGCGCGGAGC is Pathogenic according to our data. Variant chr1-1435798-T-TGGCGCGGAGCGGCGCGGAGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3031419.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5 link	c.52_71dupGCGCGGAGCGGCGCGGAGCG	p.Gly25ArgfsTer18	frameshift_variant, splice_region_variant	Exon 1 of 3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 link	c.52_71dupGCGCGGAGCGGCGCGGAGCG	p.Gly25ArgfsTer297	frameshift_variant, splice_region_variant	Exon 1 of 3		NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 link	c.52_71dupGCGCGGAGCGGCGCGGAGCG	p.Gly25ArgfsTer18	frameshift_variant, splice_region_variant	Exon 1 of 3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000471398.1 link	c.52_71dupGCGCGGAGCGGCGCGGAGCG	p.Gly25ArgfsTer58	frameshift_variant, splice_region_variant	Exon 1 of 2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 link	c.52_71dupGCGCGGAGCGGCGCGGAGCG	p.Gly25ArgfsTer297	frameshift_variant, splice_region_variant	Exon 1 of 3	2		ENSP00000423404.1	Q6PCB0-3
VWA1	ENST00000495558.1 link	c.-33+654_-33+673dupGCGCGGAGCGGCGCGGAGCG		intron_variant	Intron 1 of 1	2		ENSP00000463643.1	J3QLP3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.50e-7

AC:

AN:

1052946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

511502

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:

0.00000111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VWA1-related disorder

Pathogenic:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VWA1 c.52_71dup20 variant is predicted to result in a frameshift and premature protein termination (p.Gly25Argfs*18). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift 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

Splicing

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