Genetic Variant VWA1:p.Gly25ArgfsTer18 (chr1-1435798-T-TGGCGCGGAGCGGCGCGGAGC) – ACMG Classification: Likely_pathogenic (7 pts)

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:

LOC107985729 (HGNC:):

LOC107985729 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
LOC107985729	XM_017003066.2 link	c.648_649insGGCGCGGAGCGGCGCGGAGC		downstream_gene_variant			XP_016858555.1

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.

1-1435798-TGGCGCGGAGC-TGGCGCGGAGCGGCGCGGAGCGGCGCGGAGC

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