rs61751296
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000552.5(VWF):c.7603C>T(p.Arg2535Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
VWF
NM_000552.5 stop_gained
NM_000552.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.56
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 12-5969337-G-A is Pathogenic according to our data. Variant chr12-5969337-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5969337-G-A is described in Lovd as [Pathogenic]. Variant chr12-5969337-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.7603C>T | p.Arg2535Ter | stop_gained | 45/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.7603C>T | p.Arg2535Ter | stop_gained | 45/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.7603C>T | p.Arg2535Ter | stop_gained | 45/52 | 1 | NM_000552.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727246
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5Other:1
not provided, no classification provided | literature only | Academic Unit of Haematology, University of Sheffield | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 19, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23702511, 25525159, 1448779, 7989040, 1415226, 25673639, 16959681, 29423401, 29984440) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Nov 01, 2020 | variant already reported in ClinVar - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1992 | - - |
von Willebrand disease type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
Hereditary von Willebrand disease Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
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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