12-5969258-A-T

Position:

chr12-5969258-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000552.5(VWF):c.7682T>A(p.Phe2561Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,614,120 control chromosomes in the GnomAD database, including 1,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 143 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1582 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.10

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 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=0.0029930472).

BP6

Variant 12-5969258-A-T is Benign according to our data. Variant chr12-5969258-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 256698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5969258-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0388 (5909/152320) while in subpopulation NFE AF= 0.0493 (3356/68016). AF 95% confidence interval is 0.0479. There are 143 homozygotes in gnomad4. There are 2913 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 5909 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.7682T>A	p.Phe2561Tyr	missense_variant	45/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.7682T>A	p.Phe2561Tyr	missense_variant	45/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.7682T>A	p.Phe2561Tyr	missense_variant	45/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5907

AN:

152200

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0375

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0364

GnomAD3 exomes

AF:

0.0373

AC:

9363

AN:

251044

Hom.:

231

AF XY:

0.0376

AC XY:

5098

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00346

Gnomad FIN exome

AF:

0.0768

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0458

GnomAD4 exome

AF:

0.0437

AC:

63841

AN:

1461800

Hom.:

1582

Cov.:

AF XY:

0.0429

AC XY:

31195

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0224

Gnomad4 AMR exome

AF:

0.0256

Gnomad4 ASJ exome

AF:

0.0279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00407

Gnomad4 FIN exome

AF:

0.0773

Gnomad4 NFE exome

AF:

0.0489

Gnomad4 OTH exome

AF:

0.0375

GnomAD4 genome

AF:

0.0388

AC:

5909

AN:

152320

Hom.:

143

Cov.:

AF XY:

0.0391

AC XY:

2913

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0226

Gnomad4 AMR

AF:

0.0374

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0760

Gnomad4 NFE

AF:

0.0493

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0447

Hom.:

117

Bravo

AF:

0.0355

TwinsUK

AF:

0.0391

AC:

145

ALSPAC

AF:

0.0501

AC:

193

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.0459

AC:

395

ExAC

AF:

0.0377

AC:

4571

Asia WGS

AF:

0.00664

AC:

AN:

3476

EpiCase

AF:

0.0435

EpiControl

AF:

0.0473

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30366922) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

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

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.29

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.26

REVEL

Benign

0.11

Sift

Benign

0.53

Sift4G

Benign

0.86

Polyphen

0.11

Vest4

0.12

MPC

0.60

ClinPred

0.0072

GERP RS

4.9

Varity_R

0.10

gMVP

0.61

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