rs34444862

Positions:

chr12-5996230-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000552.5(VWF):c.5843-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,606,738 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 32)

Exomes 𝑓: 0.019 ( 321 hom. )

Consequence

VWF
NM_000552.5 splice_region, intron

Scores

Splicing: ADA: 0.0004255

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.602

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-5996230-G-C is Benign according to our data. Variant chr12-5996230-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 619939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5996230-G-C is described in Lovd as [Benign]. Variant chr12-5996230-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1882/152326) while in subpopulation NFE AF= 0.0214 (1454/68022). AF 95% confidence interval is 0.0205. There are 15 homozygotes in gnomad4. There are 842 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1882 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.5843-8C>G		splice_region_variant, intron_variant		ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.5843-8C>G		splice_region_variant, intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.5843-8C>G		splice_region_variant, intron_variant		1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-2296C>G		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1883

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.0114

AC:

2726

AN:

239088

Hom.:

AF XY:

0.0113

AC XY:

1463

AN XY:

129014

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.00400

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00251

Gnomad FIN exome

AF:

0.00902

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0120

GnomAD4 exome

AF:

0.0192

AC:

27869

AN:

1454412

Hom.:

321

Cov.:

AF XY:

0.0185

AC XY:

13376

AN XY:

722910

show subpopulations

Gnomad4 AFR exome

AF:

0.00327

Gnomad4 AMR exome

AF:

0.00459

Gnomad4 ASJ exome

AF:

0.00451

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00254

Gnomad4 FIN exome

AF:

0.00924

Gnomad4 NFE exome

AF:

0.0232

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0124

AC:

1882

AN:

152326

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

842

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00390

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00725

Gnomad4 NFE

AF:

0.0214

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary von Willebrand disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 17, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.1

DANN

Benign

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.024

SpliceAI score (max)

0.020

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