12-5949079-A-G

Position:

chr12-5949079-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting

The NM_000552.5(VWF):c.8378T>C(p.Val2793Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,614,212 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 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

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=0.0059850514).

BS2

High AC in GnomAd4 at 238 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.8378T>C	p.Val2793Ala	missense_variant	52/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.8378T>C	p.Val2793Ala	missense_variant	52/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.8378T>C	p.Val2793Ala	missense_variant	52/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.000478

GnomAD3 exomes

AF:

0.000466

AC:

117

AN:

250990

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00580

Gnomad AMR exome

AF:

0.000666

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:

0.00

GnomAD4 exome

AF:

0.000157

AC:

230

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00541

Gnomad4 AMR exome

AF:

0.000604

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:

0.00000270

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00156

AC:

238

AN:

152354

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00529

Gnomad4 AMR

AF:

0.00111

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:

0.000473

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.00195

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000445

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 31, 2017	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2022	In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general population, 0.0058 (145/24922 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; Sadler et al., 2021); This variant is associated with the following publications: (PMID: 26420797, 33556167, 22197721) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2024	Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250990 control chromosomes. c.8378T>C has been reported in the literature in healthy control individuals and Haemolytic uraemic syndrome patients (example, Bellissimo_2012, Sadler_2021, Connaughton_2023) but to our knowledge it has not been reported in individuals affected with Von Willebrand Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22197721, 37466676, 33556167). ClinVar contains an entry for this variant (Variation ID: 437264). Based on the evidence outlined above, the variant was classified as uncertain significance. -

VWF-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. 2011. PubMed ID: 22197721; Sadler et al. 2021. PubMed ID: 33556167. Table S2). This variant is reported in 0.58% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6058245-A-G). 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

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.30

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.74

M_CAP

Benign

0.046

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.31

REVEL

Benign

0.10

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.083

Vest4

0.19

MVP

0.36

MPC

0.66

ClinPred

0.043

GERP RS

5.0

Varity_R

0.27

gMVP

0.70

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