rs11063988

Positions:

chr12-6019280-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.4138A>G(p.Ile1380Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0064 in 1,613,744 control chromosomes in the GnomAD database, including 552 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 0.034 ( 299 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 253 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.231

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 -17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000552.5

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=0.006205946).

BP6

Variant 12-6019280-T-C is Benign according to our data. Variant chr12-6019280-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 310063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4138A>G	p.Ile1380Val	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1 linkuse as main transcript	c.4138A>G	p.Ile1380Val	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.4138A>G	p.Ile1380Val	missense_variant	28/52	1	NM_000552.5	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25346A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5093

AN:

151972

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0282

GnomAD3 exomes

AF:

0.00850

AC:

2124

AN:

249900

Hom.:

125

AF XY:

0.00633

AC XY:

856

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00358

AC:

5231

AN:

1461654

Hom.:

253

Cov.:

AF XY:

0.00304

AC XY:

2208

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.00588

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000359

Gnomad4 OTH exome

AF:

0.00750

GnomAD4 genome

AF:

0.0336

AC:

5103

AN:

152090

Hom.:

299

Cov.:

AF XY:

0.0326

AC XY:

2424

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.00623

Hom.:

Bravo

AF:

0.0374

ESP6500AA

AF:

0.106

AC:

468

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0104

AC:

1260

EpiCase

AF:

0.000818

EpiControl

AF:

0.000952

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2021	- -

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

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.84

DANN

Benign

0.75

DEOGEN2

Benign

0.33

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.24

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.020

REVEL

Benign

0.098

Sift

Benign

0.50

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.11

MPC

0.22

ClinPred

0.0031

GERP RS

-3.8

Varity_R

0.046

gMVP

0.46

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