chr12-6018725-C-A

Position:

chr12-6018725-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.4693G>T (p.Val1565Leu) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor REVEL gives a score of 0.183, 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 benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402474/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.094 ( 1304 hom., cov: 31)

Exomes 𝑓: 0.11 ( 12925 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.997

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 Benign. Variant got -9 ACMG points.

BP4

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4693G>T	p.Val1565Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1 linkuse as main transcript	c.4693G>T	p.Val1565Leu	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.4693G>T	p.Val1565Leu	missense_variant	28/52	1	NM_000552.5	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-24791G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0943

AC:

14342

AN:

152016

Hom.:

1294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.0374

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0849

Gnomad OTH

AF:

0.101

GnomAD3 exomes

AF:

0.154

AC:

38488

AN:

250486

Hom.:

5181

AF XY:

0.148

AC XY:

20081

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.0788

Gnomad EAS exome

AF:

0.385

Gnomad SAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.0427

Gnomad NFE exome

AF:

0.0846

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.107

AC:

156186

AN:

1460910

Hom.:

12925

Cov.:

AF XY:

0.109

AC XY:

79001

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.0177

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.0769

Gnomad4 EAS exome

AF:

0.396

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.0450

Gnomad4 NFE exome

AF:

0.0855

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.0944

AC:

14368

AN:

152134

Hom.:

1304

Cov.:

AF XY:

0.100

AC XY:

7464

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0232

Gnomad4 AMR

AF:

0.246

Gnomad4 ASJ

AF:

0.0746

Gnomad4 EAS

AF:

0.372

Gnomad4 SAS

AF:

0.218

Gnomad4 FIN

AF:

0.0374

Gnomad4 NFE

AF:

0.0849

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.0936

Hom.:

397

Bravo

AF:

0.108

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0843

AC:

325

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.0803

AC:

691

ExAC

AF:

0.144

AC:

17431

Asia WGS

AF:

0.287

AC:

995

AN:

3478

EpiCase

AF:

0.0791

EpiControl

AF:

0.0836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

von Willebrand disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.34

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.22

REVEL

Benign

0.18

Sift

Benign

0.38

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.088

MutPred

0.74

Gain of catalytic residue at V1565 (P = 0.0014);

MPC

0.27

ClinPred

0.0010

GERP RS

1.9

Varity_R

0.22

gMVP

0.76

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