1-1435798-T-TGGCGCGGAGCGGCGCGGAGC

Position:

• chr1-1435798-T-TGGCGCGGAGCGGCGCGGAGC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_022834.5(VWA1):​c.52_71dup​(p.Gly25ArgfsTer18) variant causes a frameshift 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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.706

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]

ACMG classification

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. Fraction of 0.963 CDS is truncated, and there are 1 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/exons	MANE	Protein	UniProt
VWA1	NM_022834.5	c.52_71dup	p.Gly25ArgfsTer18	frameshift_variant	1/3	ENST00000476993.2	NP_073745.2
VWA1	NM_199121.3	c.52_71dup	p.Gly25ArgfsTer297	frameshift_variant	1/3		NP_954572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA1	ENST00000476993.2	c.52_71dup	p.Gly25ArgfsTer18	frameshift_variant	1/3	1	NM_022834.5	ENSP00000417185	P1
VWA1	ENST00000338660.5	c.52_71dup	p.Gly25ArgfsTer297	frameshift_variant	1/3	2		ENSP00000423404
VWA1	ENST00000471398.1	c.52_71dup	p.Gly25ArgfsTer58	frameshift_variant	1/2	3		ENSP00000464343
VWA1	ENST00000495558.1	c.-33+654_-33+673dup		intron_variant		2		ENSP00000463643

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.50e-7 AC: 1 AN: 1052946 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 511502

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

VWA1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749383814; hg19: chr1-1371178;