rs216868

Positions:

chr12-5981998-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.7082-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,611,896 control chromosomes in the GnomAD database, including 81,704 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 Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6372 hom., cov: 31)

Exomes 𝑓: 0.31 ( 75332 hom. )

Consequence

VWF
NM_000552.5 splice_region, intron

Scores

Splicing: ADA: 0.00009456

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.843

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=-0.72).

BP6

Variant 12-5981998-G-A is Benign according to our data. Variant chr12-5981998-G-A is described in ClinVar as [Benign]. Clinvar id is 256695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5981998-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.7082-7C>T		splice_region_variant, intron_variant		ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.7082-7C>T		splice_region_variant, intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.7082-7C>T		splice_region_variant, intron_variant		1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41357

AN:

151840

Hom.:

6361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.287

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.497

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.275

GnomAD3 exomes

AF:

0.340

AC:

84017

AN:

247362

Hom.:

15551

AF XY:

0.340

AC XY:

45585

AN XY:

134162

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.471

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.497

Gnomad SAS exome

AF:

0.415

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.297

Gnomad OTH exome

AF:

0.315

GnomAD4 exome

AF:

0.313

AC:

457049

AN:

1459938

Hom.:

75332

Cov.:

AF XY:

0.316

AC XY:

229178

AN XY:

726200

show subpopulations

Gnomad4 AFR exome

AF:

0.142

Gnomad4 AMR exome

AF:

0.458

Gnomad4 ASJ exome

AF:

0.240

Gnomad4 EAS exome

AF:

0.577

Gnomad4 SAS exome

AF:

0.412

Gnomad4 FIN exome

AF:

0.306

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.272

AC:

41391

AN:

151958

Hom.:

6372

Cov.:

AF XY:

0.278

AC XY:

20671

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.152

Gnomad4 AMR

AF:

0.369

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.499

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.290

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.280

Alfa

AF:

0.287

Hom.:

2018

Bravo

AF:

0.271

Asia WGS

AF:

0.426

AC:

1482

AN:

3478

EpiCase

AF:

0.287

EpiControl

AF:

0.294

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.8

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000095

dbscSNV1_RF

Benign

0.0

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