rs267607325
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PP2PP3_StrongPP5_Moderate
The NM_000552.5(VWF):c.3430T>G(p.Trp1144Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 13)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 8.94
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 Likely_pathogenic. Variant got 9 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, 4 uncertain in NM_000552.5
PP2
?
Missense variant where missense usually causes diseases, VWF
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
?
Variant 12-6022848-A-C is Pathogenic according to our data. Variant chr12-6022848-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 100262.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6022848-A-C is described in Lovd as [Likely_pathogenic]. Variant chr12-6022848-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.3430T>G | p.Trp1144Gly | missense_variant | 26/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.3430T>G | p.Trp1144Gly | missense_variant | 26/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.3430T>G | p.Trp1144Gly | missense_variant | 26/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-28914T>G | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 13
GnomAD3 genomes
?
Cov.:
13
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 436580Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0AN XY: 231096
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
436580
Hom.:
Cov.:
2
AF XY:
AC XY:
0
AN XY:
231096
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 13
GnomAD4 genome
?
Cov.:
13
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
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 | Apr 24, 2023 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with type 1, 2, and 3 VWD (PMIDs: 16835381 (2006), 24598842 (2014), 30722078 (2019), 33556167 (2021), and 35343054 (2022)). Functional studies suggested that this variant results in reduced protein function and showed the mildest phenotype by moderate quantitative reductions of high molecular weight multimers, platelet binding strings, and platelet binding capacity (PMID: 24598842 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at Y1146 (P = 4e-04);
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