chr12-6110515-C-T

Position:

chr12-6110515-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 reported healthy control individuals with no bleeding history and normal lab values (PMID:22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. The computational predictor REVEL gives a score of 0.141, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6403810/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0061 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 13 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.97

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.391G>A	p.Gly131Ser	missense_variant	5/52	ENST00000261405.10
VWF	XM_047429501.1 linkuse as main transcript	c.391G>A	p.Gly131Ser	missense_variant	5/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.391G>A	p.Gly131Ser	missense_variant	5/52	1	NM_000552.5	P1	P04275-1
VWF	ENST00000321023.5 linkuse as main transcript	c.*450G>A		3_prime_UTR_variant, NMD_transcript_variant	6/7	1
VWF	ENST00000538635.5 linkuse as main transcript	n.420G>A		splice_region_variant, non_coding_transcript_exon_variant	5/6	4

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

918

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00187

AC:

470

AN:

251492

Hom.:

AF XY:

0.00148

AC XY:

201

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0215

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000971

AC:

1419

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

657

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0237

Gnomad4 AMR exome

AF:

0.00192

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00606

AC:

922

AN:

152248

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0203

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00656

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00211

AC:

256

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	VWF: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2022	- -

Hereditary von Willebrand disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

clinical testing

Genetics and Molecular Pathology, SA Pathology

Nov 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.21

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.5

MutationTaster

Benign

0.58

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

2.3

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.095

Vest4

0.11

MVP

0.40

MPC

0.19

ClinPred

0.0096

GERP RS

4.7

Varity_R

0.033

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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