rs144542595
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM1PP2BP4BP6BS2_Supporting
The NM_000552.5(VWF):c.8273C>T(p.Ala2758Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 7.16
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
?
In a disulfide_bond (size 50) in uniprot entity VWF_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000552.5
PP2
?
Missense variant where missense usually causes diseases, VWF
BP4
?
Computational evidence support a benign effect (MetaRNN=0.26487482).
BP6
?
Variant 12-5949184-G-A is Benign according to our data. Variant chr12-5949184-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
?
High AC in GnomAd4 at 11 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.8273C>T | p.Ala2758Val | missense_variant | 52/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.8273C>T | p.Ala2758Val | missense_variant | 52/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.8273C>T | p.Ala2758Val | missense_variant | 52/52 | 1 | NM_000552.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000722 AC: 11AN: 152262Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250790Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135612
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461762Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727180
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GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 31, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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