chr12-6044368-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 5P and 20B. PM1PM5PP2BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.2365A>G(p.Thr789Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,858 control chromosomes in the GnomAD database, including 107,997 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T789P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.40 ( 13217 hom., cov: 33)

Exomes 𝑓: 0.35 ( 94780 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 0.942

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 -15 ACMG points.

PM1

In a domain TIL 3 (size 51) in uniprot entity VWF_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000552.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6044368-T-G is described in Lovd as [Likely_pathogenic].

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=6.430792E-5).

BP6

Variant 12-6044368-T-C is Benign according to our data. Variant chr12-6044368-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6044368-T-C is described in Lovd as [Benign]. Variant chr12-6044368-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2365A>G	p.Thr789Ala	missense_variant	Exon 18 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2365A>G	p.Thr789Ala	missense_variant	Exon 18 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2365A>G	p.Thr789Ala	missense_variant	Exon 18 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-50434A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.395

AC:

60042

AN:

151930

Hom.:

13190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.576

Gnomad AMI

AF:

0.386

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.295

Gnomad EAS

AF:

0.0782

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.372

GnomAD3 exomes

AF:

0.312

AC:

78459

AN:

251226

Hom.:

14078

AF XY:

0.311

AC XY:

42243

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.0702

Gnomad SAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.324

GnomAD4 exome

AF:

0.352

AC:

514079

AN:

1461810

Hom.:

94780

Cov.:

AF XY:

0.348

AC XY:

253379

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.583

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.0709

Gnomad4 SAS exome

AF:

0.249

Gnomad4 FIN exome

AF:

0.358

Gnomad4 NFE exome

AF:

0.371

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.395

AC:

60108

AN:

152048

Hom.:

13217

Cov.:

AF XY:

0.387

AC XY:

28788

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.576

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.295

Gnomad4 EAS

AF:

0.0774

Gnomad4 SAS

AF:

0.236

Gnomad4 FIN

AF:

0.354

Gnomad4 NFE

AF:

0.362

Gnomad4 OTH

AF:

0.368

Alfa

AF:

0.357

Hom.:

25219

Bravo

AF:

0.400

TwinsUK

AF:

0.370

AC:

1372

ALSPAC

AF:

0.377

AC:

1453

ESP6500AA

AF:

0.568

AC:

2504

ESP6500EA

AF:

0.357

AC:

3074

ExAC

AF:

0.323

AC:

39189

Asia WGS

AF:

0.204

AC:

710

AN:

3478

EpiCase

AF:

0.354

EpiControl

AF:

0.362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32521332, 30817071, 30046743, 18923835, 23636243, 21163921, 23690449, 21534939) -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 58.215% in gnomAD_Exomes) 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. -

Mar 02, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

von Willebrand disease type 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.35

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.046

MetaRNN

Benign

0.000064

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

0.94

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.048

MPC

0.18

ClinPred

0.00037

GERP RS

2.2

Varity_R

0.17

gMVP

0.55

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