12-5949044-T-TGGGGA

Position:

• chr12-5949044-T-TGGGGA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000552.5(VWF):​c.8412_8413insTCCCC​(p.Lys2805SerfsTer46) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.06

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon NOT found. This looks like a Nonstop Mediated Decay case. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.8412_8413insTCCCC	p.Lys2805SerfsTer46	frameshift_variant	52/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.8412_8413insTCCCC	p.Lys2805SerfsTer46	frameshift_variant	52/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.8412_8413insTCCCC	p.Lys2805SerfsTer46	frameshift_variant	52/52	1	NM_000552.5	ENSP00000261405	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

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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: rs267607371; hg19: chr12-6058210;