rs143904314

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The ENST00000261405.10(VWF):ā€‹c.2340C>Gā€‹(p.Asn780Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,614,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00067 ( 0 hom., cov: 33)
Exomes š‘“: 0.000074 ( 0 hom. )

Consequence

VWF
ENST00000261405.10 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.33
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1
In a domain TIL 3 (size 51) in uniprot entity VWF_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in ENST00000261405.10
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.05134633).
BS2
High AC in GnomAd4 at 102 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 Protein UniProt
VWFNM_000552.5 linkuse as main transcriptc.2340C>G p.Asn780Lys missense_variant 18/52 ENST00000261405.10 NP_000543.3
VWFXM_047429501.1 linkuse as main transcriptc.2340C>G p.Asn780Lys missense_variant 18/52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkuse as main transcriptc.2340C>G p.Asn780Lys missense_variant 18/521 NM_000552.5 ENSP00000261405 P1P04275-1
VWFENST00000538635.5 linkuse as main transcriptn.421-50459C>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.000664
AC:
101
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000187
AC:
47
AN:
251352
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00258
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000739
AC:
108
AN:
1461890
Hom.:
0
Cov.:
35
AF XY:
0.0000688
AC XY:
50
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00260
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000281
GnomAD4 genome
AF:
0.000670
AC:
102
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.000523
AC XY:
39
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00243
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000170
Hom.:
0
Bravo
AF:
0.000899
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000305
AC:
37

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 20, 2023Variant summary: VWF c.2340C>G (p.Asn780Lys) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251352 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2340C>G in individuals affected with Von Willebrand Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 19, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 16, 2023In the published literature, this variant has been reported in healthy individuals (PMIDs: 3342085 (2020), 23690449 (2013)). The frequency of this variant in the general population, 0.003 (75/24960 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
VWF-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 29, 2024The VWF c.2340C>G variant is predicted to result in the amino acid substitution p.Asn780Lys. To our knowledge, this variant has not been reported in VWF related disease. This variant is reported in 0.30% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
0.091
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.87
D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.051
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.29
Sift
Benign
0.085
T
Sift4G
Benign
0.098
T
Polyphen
0.61
P
Vest4
0.63
MutPred
0.47
Gain of ubiquitination at N780 (P = 0.0094);
MVP
0.71
MPC
0.79
ClinPred
0.021
T
GERP RS
3.3
Varity_R
0.23
gMVP
0.80

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: rs143904314; hg19: chr12-6153559; API