rs143054357

Positions:

chr12-6095571-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_000552.5(VWF):c.546G>A(p.Ser182Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,110 control chromosomes in the GnomAD database, including 6 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 0.0012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -4.13

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:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP6

Variant 12-6095571-C-T is Benign according to our data. Variant chr12-6095571-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

BS2

High AC in GnomAd4 at 186 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/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.546G>A	p.Ser182Ser	synonymous_variant	6/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.546G>A	p.Ser182Ser	synonymous_variant	6/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.546G>A	p.Ser182Ser	synonymous_variant	6/52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000321023.5 linkuse as main transcript	n.*605G>A		non_coding_transcript_exon_variant	7/7	1		ENSP00000461331.1	I3L4K4
VWF	ENST00000321023.5 linkuse as main transcript	n.*605G>A		3_prime_UTR_variant	7/7	1		ENSP00000461331.1	I3L4K4
VWF	ENST00000538635.5 linkuse as main transcript	n.420+14944G>A		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00124

AC:

312

AN:

251476

Hom.:

AF XY:

0.00127

AC XY:

173

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00246

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00161

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00148

AC:

2159

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1053

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00168

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152248

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00179

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00146

Hom.:

Bravo

AF:

0.00128

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Observed with a variant on the opposite allele (in trans) in a patient with type 1 von Willebrand disease (VWD) in the published literature (Borrs et al., 2019), and observed with a variant in cis and a variant in trans in a patient with type 3 VWD in the published literature (Corrales et al., 2009; Borrs et al., 2019); Published functional studies demonstrate a damaging effect by affect splicing of VWF mRNA (Borrs et al., 2019); This variant is associated with the following publications: (PMID: 19277422, 36307006, 34708896, 30361419) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2023	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2023	- -

von Willebrand disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Nov 26, 2021

- -

von Willebrand disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.025

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.41

Position offset: 13

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