rs267607326
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong
The NM_000552.5(VWF):c.3437A>G(p.Tyr1146Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 12)
Exomes 𝑓: 0.0000023 ( 0 hom. )
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 3.87
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 15 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000552.5
PP2
?
Missense variant where missense usually causes diseases, VWF
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant 12-6022841-T-C is Pathogenic according to our data. Variant chr12-6022841-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 31009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6022841-T-C is described in Lovd as [Likely_pathogenic]. Variant chr12-6022841-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.3437A>G | p.Tyr1146Cys | missense_variant | 26/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.3437A>G | p.Tyr1146Cys | missense_variant | 26/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.3437A>G | p.Tyr1146Cys | missense_variant | 26/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-28907A>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 12
GnomAD3 genomes
?
Cov.:
12
GnomAD4 exome AF: 0.00000227 AC: 1AN: 440372Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0AN XY: 232952
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AN XY:
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GnomAD4 genome ? Cov.: 12
GnomAD4 genome
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Cov.:
12
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
von Willebrand disease type 2 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Apr 26, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 10, 2010 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
Hereditary von Willebrand disease Pathogenic:2
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2022 | Variant summary: VWF c.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54460 control chromosomes. c.3437A>G has been reported in the literature in multiple individuals affected with Type I and Type II Von Willebrand Disease (example, Goodeve_2007, Castaman_2008, James_2007, Schneppenheim_2010, Manderstedt_2018, Fidalgo_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in inhibition of normal processing, string formation and platelet binding (Brehm_2014), defective intracellular packaging and markedly reduced VWF secretion. Loss of HMW Multimers. Demonstrated a novel FVIII binding defect (White-Adams_2016) and reduced expression (Schneppenheim_2010). One clinical diagnostic laboratory and the NIHR Bioresource Rare Diseases have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 25, 2020 | The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 (2007), 17190853 (2007), 20351307 (2010), 22871923 (2012), 26986123 (2016), 26988807 (2016), 29388750 (2018), 29742318 (2018), 31249928 (2018), 31064749 (2019)). Functional studies showed that this variant caused defective intracellular packaging, reduced VWF secretion, and a FVIII binding defect as well as loss of large multimers and decreased proteolysis (PMID: 18230755 (2008), 20351307 (2010), 24598842 (2014), 27533707 (2016)). Therefore, the variant is classified as pathogenic. - |
von Willebrand disease type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
not provided Other:1
not provided, no classification provided | literature only | Academic Unit of Haematology, University of Sheffield | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at E1143 (P = 0.0192);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at