rs55687637

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000552.5(VWF):​c.7887+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,368 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0081 ( 7 hom., cov: 32)
Exomes 𝑓: 0.010 ( 90 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.953
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 12-5967474-A-G is Benign according to our data. Variant chr12-5967474-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256701.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr12-5967474-A-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00809 (1231/152200) while in subpopulation NFE AF= 0.0124 (844/67984). AF 95% confidence interval is 0.0117. There are 7 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1231 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.7887+12T>C intron_variant Intron 47 of 51 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.7887+12T>C intron_variant Intron 47 of 51 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.7887+12T>C intron_variant Intron 47 of 51 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000621700.1 linkn.205+12T>C intron_variant Intron 2 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.00810
AC:
1232
AN:
152082
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00193
Gnomad AMI
AF:
0.0407
Gnomad AMR
AF:
0.00760
Gnomad ASJ
AF:
0.0112
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00764
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0124
Gnomad OTH
AF:
0.0110
GnomAD3 exomes
AF:
0.00777
AC:
1951
AN:
251224
Hom.:
13
AF XY:
0.00772
AC XY:
1049
AN XY:
135824
show subpopulations
Gnomad AFR exome
AF:
0.00277
Gnomad AMR exome
AF:
0.00517
Gnomad ASJ exome
AF:
0.0112
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00225
Gnomad FIN exome
AF:
0.00767
Gnomad NFE exome
AF:
0.0117
Gnomad OTH exome
AF:
0.00798
GnomAD4 exome
AF:
0.0103
AC:
15017
AN:
1461168
Hom.:
90
Cov.:
32
AF XY:
0.0102
AC XY:
7397
AN XY:
726942
show subpopulations
Gnomad4 AFR exome
AF:
0.00158
Gnomad4 AMR exome
AF:
0.00566
Gnomad4 ASJ exome
AF:
0.0107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00239
Gnomad4 FIN exome
AF:
0.00714
Gnomad4 NFE exome
AF:
0.0119
Gnomad4 OTH exome
AF:
0.00952
GnomAD4 genome
AF:
0.00809
AC:
1231
AN:
152200
Hom.:
7
Cov.:
32
AF XY:
0.00775
AC XY:
577
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.00193
Gnomad4 AMR
AF:
0.00759
Gnomad4 ASJ
AF:
0.0112
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00764
Gnomad4 NFE
AF:
0.0124
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.00991
Hom.:
2
Bravo
AF:
0.00804
Asia WGS
AF:
0.00144
AC:
6
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:3
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
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

- -

not provided Benign:2
Sep 20, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

VWF: BS1, BS2 -

Hereditary von Willebrand disease Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
2.0
DANN
Benign
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.

Other links and lift over

dbSNP: rs55687637; hg19: chr12-6076640; API