chr12-6063036-T-C

Position:

chr12-6063036-T-C

Variant summary

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

The NM_000552.5(VWF):c.1451A>G(p.His484Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,612,716 control chromosomes in the GnomAD database, including 327,980 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 0.53 ( 24306 hom., cov: 32)

Exomes 𝑓: 0.64 ( 303674 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 0.268

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 Benign. Variant got -19 ACMG points.

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=7.129097E-6).

BP6

Variant 12-6063036-T-C is Benign according to our data. Variant chr12-6063036-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6063036-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1451A>G	p.His484Arg	missense_variant	13/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1451A>G	p.His484Arg	missense_variant	13/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.1451A>G	p.His484Arg	missense_variant	13/52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+47479A>G		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

80019

AN:

151984

Hom.:

24308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.656

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.722

Gnomad EAS

AF:

0.692

Gnomad SAS

AF:

0.707

Gnomad FIN

AF:

0.674

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.657

Gnomad OTH

AF:

0.566

GnomAD3 exomes

AF:

0.621

AC:

155009

AN:

249536

Hom.:

50166

AF XY:

0.638

AC XY:

86153

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.524

Gnomad ASJ exome

AF:

0.733

Gnomad EAS exome

AF:

0.704

Gnomad SAS exome

AF:

0.708

Gnomad FIN exome

AF:

0.671

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.650

GnomAD4 exome

AF:

0.640

AC:

934494

AN:

1460614

Hom.:

303674

Cov.:

AF XY:

0.644

AC XY:

468245

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.200

Gnomad4 AMR exome

AF:

0.526

Gnomad4 ASJ exome

AF:

0.729

Gnomad4 EAS exome

AF:

0.670

Gnomad4 SAS exome

AF:

0.705

Gnomad4 FIN exome

AF:

0.667

Gnomad4 NFE exome

AF:

0.648

Gnomad4 OTH exome

AF:

0.628

GnomAD4 genome

AF:

0.526

AC:

80033

AN:

152102

Hom.:

24306

Cov.:

AF XY:

0.532

AC XY:

39557

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.541

Gnomad4 ASJ

AF:

0.722

Gnomad4 EAS

AF:

0.692

Gnomad4 SAS

AF:

0.707

Gnomad4 FIN

AF:

0.674

Gnomad4 NFE

AF:

0.657

Gnomad4 OTH

AF:

0.562

Alfa

AF:

0.642

Hom.:

72717

Bravo

AF:

0.502

TwinsUK

AF:

0.650

AC:

2411

ALSPAC

AF:

0.664

AC:

2559

ESP6500AA

AF:

0.219

AC:

966

ESP6500EA

AF:

0.657

AC:

5649

ExAC

AF:

0.618

AC:

75019

Asia WGS

AF:

0.615

AC:

2138

AN:

3478

EpiCase

AF:

0.665

EpiControl

AF:

0.662

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 73.314% in gnomAD_ExomesFounderPop) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

0.062

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.8

DANN

Benign

0.54

DEOGEN2

Benign

0.23

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0000071

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.41

PrimateAI

Benign

0.34

PROVEAN

Benign

1.7

REVEL

Benign

0.063

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.017

Vest4

0.062

MPC

0.30

ClinPred

0.0019

GERP RS

1.3

Varity_R

0.057

gMVP

0.47

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