rs143904314

Positions:

chr12-6044393-G-C

Variant summary

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

The NM_000552.5(VWF):c.2340C>G(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 (★★).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

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]

VWF links:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a disulfide_bond (size 28) in uniprot entity VWF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000552.5

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
VWF	NM_000552.5 linkuse as main transcript	c.2340C>G	p.Asn780Lys	missense_variant	18/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.2340C>G	p.Asn780Lys	missense_variant	18/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.2340C>G	p.Asn780Lys	missense_variant	18/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-50459C>G		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152216

Hom.:

Cov.:

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:

AN:

251352

Hom.:

AF XY:

0.000118

AC XY:

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.:

Cov.:

AF XY:

0.0000688

AC XY:

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.:

Cov.:

AF XY:

0.000523

AC XY:

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.:

Bravo

AF:

0.000899

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

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 submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2023	Variant 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 16, 2023

In 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 provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

The 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

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.091

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

REVEL

Benign

0.29

Sift

Benign

0.085

Sift4G

Benign

0.098

Polyphen

0.61

Vest4

0.63

MutPred

0.47

Gain of ubiquitination at N780 (P = 0.0094);

MVP

0.71

MPC

0.79

ClinPred

0.021

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over