rs1800387

Positions:

chr12-6073662-A-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.954T>A(p.Asn318Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,613,830 control chromosomes in the GnomAD database, including 8,471 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 0.14 ( 3887 hom., cov: 31)

Exomes 𝑓: 0.041 ( 4584 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.129

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=0.003455609).

BP6

Variant 12-6073662-A-T is Benign according to our data. Variant chr12-6073662-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 198745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6073662-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 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.954T>A	p.Asn318Lys	missense_variant	8/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.954T>A	p.Asn318Lys	missense_variant	8/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.954T>A	p.Asn318Lys	missense_variant	8/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.420+36853T>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21782

AN:

151860

Hom.:

3879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0795

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0635

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0295

Gnomad OTH

AF:

0.118

GnomAD3 exomes

AF:

0.0612

AC:

15377

AN:

251422

Hom.:

1752

AF XY:

0.0564

AC XY:

7666

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.434

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.0562

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0790

Gnomad FIN exome

AF:

0.0199

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0511

GnomAD4 exome

AF:

0.0414

AC:

60463

AN:

1461852

Hom.:

4584

Cov.:

AF XY:

0.0416

AC XY:

30246

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.447

Gnomad4 AMR exome

AF:

0.0445

Gnomad4 ASJ exome

AF:

0.0573

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0789

Gnomad4 FIN exome

AF:

0.0185

Gnomad4 NFE exome

AF:

0.0271

Gnomad4 OTH exome

AF:

0.0579

GnomAD4 genome

AF:

0.144

AC:

21820

AN:

151978

Hom.:

3887

Cov.:

AF XY:

0.140

AC XY:

10402

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.426

Gnomad4 AMR

AF:

0.0794

Gnomad4 ASJ

AF:

0.0499

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0637

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.0295

Gnomad4 OTH

AF:

0.118

Alfa

AF:

0.0467

Hom.:

460

Bravo

AF:

0.161

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.412

AC:

1814

ESP6500EA

AF:

0.0258

AC:

222

ExAC

AF:

0.0690

AC:

8382

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

EpiCase

AF:

0.0321

EpiControl

AF:

0.0335

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	This variant is associated with the following publications: (PMID: 27884173, 24675615) -

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

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

REVEL

Benign

0.26

Sift

Benign

0.24

Sift4G

Benign

0.27

Polyphen

0.77

Vest4

0.082

MutPred

0.58

Gain of methylation at N318 (P = 0.0037);

MPC

0.31

ClinPred

0.0048

GERP RS

-3.5

Varity_R

0.13

gMVP

0.36

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