rs1800377

Positions:

chr12-6064267-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.1411G>A(p.Val471Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,614,044 control chromosomes in the GnomAD database, including 11,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1091 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10753 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00400

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 Benign. Variant got -19 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=0.0015455186).

BP6

Variant 12-6064267-C-T is Benign according to our data. Variant chr12-6064267-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.1411G>A	p.Val471Ile	missense_variant	12/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.1411G>A	p.Val471Ile	missense_variant	12/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.1411G>A	p.Val471Ile	missense_variant	12/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.420+46248G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17587

AN:

152142

Hom.:

1092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0625

Gnomad ASJ

AF:

0.0424

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.0930

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0918

GnomAD3 exomes

AF:

0.114

AC:

28579

AN:

250654

Hom.:

1926

AF XY:

0.118

AC XY:

16043

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.0483

Gnomad ASJ exome

AF:

0.0507

Gnomad EAS exome

AF:

0.171

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.0983

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.117

AC:

171222

AN:

1461782

Hom.:

10753

Cov.:

AF XY:

0.119

AC XY:

86576

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0501

Gnomad4 ASJ exome

AF:

0.0490

Gnomad4 EAS exome

AF:

0.163

Gnomad4 SAS exome

AF:

0.175

Gnomad4 FIN exome

AF:

0.0995

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.116

AC:

17590

AN:

152262

Hom.:

1091

Cov.:

AF XY:

0.114

AC XY:

8474

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.139

Gnomad4 AMR

AF:

0.0623

Gnomad4 ASJ

AF:

0.0424

Gnomad4 EAS

AF:

0.169

Gnomad4 SAS

AF:

0.176

Gnomad4 FIN

AF:

0.0930

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.0908

Alfa

AF:

0.111

Hom.:

1572

Bravo

AF:

0.112

TwinsUK

AF:

0.115

AC:

427

ALSPAC

AF:

0.111

AC:

428

ESP6500AA

AF:

0.139

AC:

611

ESP6500EA

AF:

0.110

AC:

948

ExAC

AF:

0.118

AC:

14348

Asia WGS

AF:

0.166

AC:

576

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2018	- -

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

0.068

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.2

DANN

Benign

0.40

DEOGEN2

Benign

0.25

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.055

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.37

REVEL

Benign

0.13

Sift

Benign

0.96

Sift4G

Benign

1.0

Polyphen

0.019

Vest4

0.038

MPC

0.21

ClinPred

0.0031

GERP RS

-2.9

Varity_R

0.032

gMVP

0.12

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