chr1-1436948-GA-G

Position:

• chr1-1436948-GA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_022834.5(VWA1):​c.96delA​(p.Asp34fs) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VWA1 NM_022834.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.240

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 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 1-1436948-GA-G is Pathogenic according to our data. Variant chr1-1436948-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 2154860.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	c.96delA	p.Asp34fs	frameshift_variant	2/3	ENST00000476993.2	NP_073745.2
VWA1	NM_199121.3	c.74-373delA		intron_variant			NP_954572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA1	ENST00000476993.2	c.96delA	p.Asp34fs	frameshift_variant	2/3	1	NM_022834.5	ENSP00000417185.1
VWA1	ENST00000471398.1	c.216delA	p.Asp74fs	frameshift_variant	2/2	3		ENSP00000464343.1
VWA1	ENST00000495558	c.-10delA		5_prime_UTR_variant	2/2	2		ENSP00000463643.1
VWA1	ENST00000338660.5	c.74-373delA		intron_variant		2		ENSP00000423404.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

This sequence change creates a premature translational stop signal (p.Asp34Thrfs*2) in the VWA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VWA1 are known to be pathogenic (PMID: 33459760). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VWA1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1372328;