rs61750079

chr12-6019180-G-Achr12-6019180-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate

The NM_000552.5(VWF):c.4238C>T(p.Pro1413Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1413Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 9.23

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000552.5

PP2

Missense variant where missense usually causes diseases, VWF

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4238C>T	p.Pro1413Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1 linkuse as main transcript	c.4238C>T	p.Pro1413Leu	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.4238C>T	p.Pro1413Leu	missense_variant	28/52	1	NM_000552.5	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25246C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251134

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

VWF-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2022

The VWF c.4238C>T variant is predicted to result in the amino acid substitution p.Pro1413Leu. This variant has been reported in individuals with Von Willebrand disease 1 (Goodeve et al. 2007. PubMed ID: 16985174; Manderstedt et al. 2018. PubMed ID: 31249928; Dubois et al. 2020. PubMed ID: 33134807). In Manderstedt et al., this variant occurred together with another variant (p.Gly1672Arg), indicating these two variants occur on the same haplotype (Manderstedt et al. 2018. PubMed ID: 31249928). Functional studies using protein expression in cell culture found that the p.Pro1413Leu substitution did not significantly affect protein function (Berber et al. 2016. PubMed ID: 27483487). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6128346-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.63

MutPred

0.71

Gain of catalytic residue at G1417 (P = 0);

MVP

0.95

MPC

0.95

ClinPred

0.99

GERP RS

4.9

Varity_R

0.64

gMVP

0.86

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