rs62643632
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000552.5(VWF):βc.2435delCβ(p.Pro812fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000059 ( 0 hom., cov: 32)
Exomes π: 0.000073 ( 0 hom. )
Consequence
VWF
NM_000552.5 frameshift
NM_000552.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.02
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 12-6044297-CG-C is Pathogenic according to our data. Variant chr12-6044297-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6044297-CG-C is described in Lovd as [Pathogenic]. Variant chr12-6044297-CG-C is described in Lovd as [Pathogenic]. Variant chr12-6044297-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000112 AC: 28AN: 250878Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135654
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GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461760Hom.: 0 Cov.: 30 AF XY: 0.0000853 AC XY: 62AN XY: 727172
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74322
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | VWF: PVS1, PM2 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided, no classification provided | literature only | Academic Unit of Haematology, University of Sheffield | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 09, 2023 | This frameshift variant alters the translational reading frame of the VWF mRNA and causes the premature termination of VWF protein synthesis. The frequency of this variant in the general population, 0.00054 (14/26126 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been described as a common mutation in the Swedish and Finnish populations (PMIDs: 1302613 (1992), 23834637 (2013)), reported in heterozygous patients with vWD type I (PMIDs: 16985174 (2007), 17190853 (2007)), and in homozygous or compound heterozygous patients with vWD type III (PMIDs: 23834637 (2013), 29427305 (2018), 35343054 (2022)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 10, 2018 | - - |
von Willebrand disease type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Mar 09, 2024 | ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 25, 2023 | Criteria applied: PVS1,PS4,PS3_MOD - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
von Willebrand disease type 3 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Apr 12, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 20, 1993 | - - |
Hereditary von Willebrand disease Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
von Willebrand disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 11, 2024 | Criteria applied: PVS1,PM3,PM2_SUP; Identified as compund heterozygous with NM_000552.5:c.2561G>A - |
von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Abnormal bleeding Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at