rs566672558
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2
The NM_000552.5(VWF):c.3485C>T(p.Pro1162Leu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1162P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.054 ( 530 hom., cov: 11)
Exomes 𝑓: 0.0082 ( 275 hom. )
Failed GnomAD Quality Control
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
5
9
4
Clinical Significance
Conservation
PhyloP100: 6.35
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 Benign. Variant got -13 ACMG points.
PM1
?
In a domain TIL 4 (size 50) in uniprot entity VWF_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in NM_000552.5
PP2
?
Missense variant where missense usually causes diseases, VWF
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0019468367).
BP6
?
Variant 12-6022793-G-A is Benign according to our data. Variant chr12-6022793-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6022793-G-A is described in Lovd as [Benign].
BS2
?
High AC in GnomAd at 4858 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.3485C>T | p.Pro1162Leu | missense_variant | 26/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.3485C>T | p.Pro1162Leu | missense_variant | 26/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.3485C>T | p.Pro1162Leu | missense_variant | 26/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-28859C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0539 AC: 4858AN: 90098Hom.: 528 Cov.: 11
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GnomAD3 exomes AF: 0.0256 AC: 1391AN: 54328Hom.: 125 AF XY: 0.0228 AC XY: 624AN XY: 27388
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00824 AC: 3629AN: 440470Hom.: 275 Cov.: 0 AF XY: 0.00701 AC XY: 1628AN XY: 232400
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0540 AC: 4870AN: 90138Hom.: 530 Cov.: 11 AF XY: 0.0542 AC XY: 2167AN XY: 39996
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
von Willebrand disease type 1 Benign:1
Benign, criteria provided, single submitter | research | Laboratory of Hematology, Radboud University Medical Center | Dec 10, 2020 | - - |
Hereditary von Willebrand disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
P
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
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