NM_000552.5:c.8341C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000552.5(VWF):​c.8341C>T​(p.Pro2781Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

VWF
NM_000552.5 missense

Scores

8
11

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 2.65
Variant links:
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.31456596).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.8341C>T p.Pro2781Ser missense_variant Exon 52 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.8341C>T p.Pro2781Ser missense_variant Exon 52 of 52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.8341C>T p.Pro2781Ser missense_variant Exon 52 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not provided Other:1
-
Academic Unit of Haematology, University of Sheffield
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.11
Sift
Benign
0.14
T
Sift4G
Uncertain
0.044
D
Polyphen
0.94
P
Vest4
0.15
MutPred
0.42
Gain of catalytic residue at R2778 (P = 0.0289);
MVP
0.75
MPC
0.28
ClinPred
0.62
D
GERP RS
4.9
Varity_R
0.26
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61751313; hg19: chr12-6058282; API