chr12-5949034-G-GGGGA

Variant names:

• chr12-5949034-G-GGGGA
• rs1414503929
• NM_000552.5:c.8419_8422dupTCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1_Moderate PP5_Very_Strong BS2_Supporting

The NM_000552.5(VWF):​c.8419_8422dupTCCC​(p.Pro2808LeufsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: VWF NM_000552.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.807

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00237 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 12-5949034-G-GGGGA is Pathogenic according to our data. Variant chr12-5949034-G-GGGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2628675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.8419_8422dupTCCC	p.Pro2808LeufsTer24	frameshift_variant	Exon 52 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.8419_8422dupTCCC	p.Pro2808LeufsTer24	frameshift_variant	Exon 52 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.8419_8422dupTCCC	p.Pro2808LeufsTer24	frameshift_variant	Exon 52 of 52	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461252 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726872

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33470

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44636

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26108

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39686

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86116

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53356

Gnomad4 NFE exome AF: 0.00000540 AC: 6 AN: 1111794

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014699 AN: 0.000014699

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 6 amino acids are replaced with 23 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28453889, 33550700, 17190853, 35343054, 23311757) -

VWF-related disorder Pathogenic:1

Apr 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.8419_8422dupTCCC variant is predicted to result in a frameshift and premature protein termination (p.Pro2808Leufs*24). XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX which is predicted to result in a frameshift and extension of the normal open reading frame (p.Pro2808Leufs*24) (the canonical stop codon is at position p.2814). This variant has been reported in individuals with von Willebrand disease 1 (James et al. 2007. PubMed ID: 17190853). This variant has also been reported in the homozygous or compound heterozygous states in multiple individuals with von Willebrand disease 3 (Bowman et al. 2013. PubMed ID: 23311757; Bowman et al. 2017. PubMed ID: 28453889). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=4/196	disease causing

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1414503929; hg19: chr12-6058200;