12-6019298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_000552.5(VWF):​c.4120C>A​(p.Arg1374Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1374C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

VWF
NM_000552.5 missense

Scores

13
3
3

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.01
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 Pathogenic. Variant got 11 ACMG points.

PM1
In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000552.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-6019298-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VWFNM_000552.5 linkuse as main transcriptc.4120C>A p.Arg1374Ser missense_variant 28/52 ENST00000261405.10 NP_000543.3
VWFXM_047429501.1 linkuse as main transcriptc.4120C>A p.Arg1374Ser missense_variant 28/52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkuse as main transcriptc.4120C>A p.Arg1374Ser missense_variant 28/521 NM_000552.5 ENSP00000261405 P1P04275-1
VWFENST00000538635.5 linkuse as main transcriptn.421-25364C>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
38
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Other:1
not provided, no classification providedliterature onlyAcademic Unit of Haematology, University of Sheffield-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.8
N
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.80
Gain of catalytic residue at K1371 (P = 0.0031);
MVP
0.96
MPC
0.97
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.82
gMVP
0.89

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: rs61750071; hg19: chr12-6128464; API