rs78353028

Positions:

chr12-5952509-G-A

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(VWF):c.7997C>T is a missense variant that substitutes threonine for methionine at position 2666. The Grpmax filtering allele frequency in gnomAD v4.0 is 0.06826 (based on 5238/74998 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). While this variant has been observed in healthy control individuals (PMID:22197721), BS2 is not being used due to penetrance issues. The computational predictor REVEL gives a score of 0.027, 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 likely benign for 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/CA6401422/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.020 ( 96 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 95 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.519

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 -5 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.7997C>T	p.Thr2666Met	missense_variant	49/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.7997C>T	p.Thr2666Met	missense_variant	49/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.7997C>T	p.Thr2666Met	missense_variant	49/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000612016.1 linkuse as main transcript	n.406C>T		non_coding_transcript_exon_variant	2/3	5
VWF	ENST00000621700.1 linkuse as main transcript	n.315C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.0204

AC:

3100

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0706

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00513

AC:

1290

AN:

251334

Hom.:

AF XY:

0.00388

AC XY:

527

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0679

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00206

AC:

3012

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1291

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0691

Gnomad4 AMR exome

AF:

0.00427

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.00487

GnomAD4 genome

AF:

0.0204

AC:

3099

AN:

152284

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1454

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0704

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.0236

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0685

AC:

302

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00605

AC:

735

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 25, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

VWF-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

0.071

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Uncertain

0.68

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.57

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.027

Sift

Benign

0.21

Sift4G

Benign

0.15

Polyphen

0.0090

Vest4

0.065

MVP

0.48

MPC

0.28

ClinPred

0.0040

GERP RS

0.38

Varity_R

0.033

gMVP

0.73

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