rs138900040

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The NM_000552.5(VWF):c.3868G>A(p.Glu1290Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.98

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a helix (size 15) in uniprot entity VWF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000552.5

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=0.03959188).

BS2

High AC in GnomAd4 at 89 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.3868G>A	p.Glu1290Lys	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.3868G>A	p.Glu1290Lys	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.3868G>A	p.Glu1290Lys	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000539641.1 link	n.666G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3
VWF	ENST00000538635.5 link	n.421-25616G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251084

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000584

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000722

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 15, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWF c.3868G>A; p.Glu1290Lys variant (rs138900040), to our knowledge, is not reported in the medical literature or gene-specific databases in association with von Willebrand disease. This variant is found in the African population with an overall allele frequency of 0.25% (63/24954 alleles) in the Genome Aggregation Database. The glutamate at codon 1290 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, although a modeling study incorporating population data and VWF levels suggested the p.Glu1290Lys variant had a low probability of being disease-causing (Cheng 2016). However, given the lack of clinical and functional data, the significance of the p.Glu1290Lys variant is uncertain at this time. References: Cheng Y et al. Group association test using a hidden Markov model. Biostatistics. 2016 Apr;17(2):221-34. -

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VWF p.Glu1290Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138900040) and in ClinVar (classified as a VUS by Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in control databases in 71 of 282484 chromosomes at a frequency of 0.000251 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 63 of 24954 chromosomes (freq: 0.002525), Latino in 5 of 35440 chromosomes (freq: 0.000141), South Asian in 2 of 30616 chromosomes (freq: 0.000065) and European (non-Finnish) in 1 of 128814 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu1290 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.040

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.48

MVP

0.82

MPC

0.79

ClinPred

0.16

GERP RS

3.3

Varity_R

0.45

gMVP

0.93

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