12-6044348-A-G

Position:

chr12-6044348-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.2385T>C(p.Tyr795=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,920 control chromosomes in the GnomAD database, including 108,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13207 hom., cov: 33)

Exomes 𝑓: 0.35 ( 94802 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: -1.14

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 12-6044348-A-G is Benign according to our data. Variant chr12-6044348-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6044348-A-G is described in Lovd as [Benign]. Variant chr12-6044348-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 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.2385T>C	p.Tyr795=	synonymous_variant	18/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.2385T>C	p.Tyr795=	synonymous_variant	18/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.2385T>C	p.Tyr795=	synonymous_variant	18/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-50414T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.395

AC:

60027

AN:

151964

Hom.:

13180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.576

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.0782

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.372

GnomAD3 exomes

AF:

0.312

AC:

78487

AN:

251290

Hom.:

14095

AF XY:

0.311

AC XY:

42261

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.0702

Gnomad SAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.324

GnomAD4 exome

AF:

0.352

AC:

514131

AN:

1461838

Hom.:

94802

Cov.:

AF XY:

0.348

AC XY:

253414

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.583

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.0709

Gnomad4 SAS exome

AF:

0.249

Gnomad4 FIN exome

AF:

0.358

Gnomad4 NFE exome

AF:

0.371

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.395

AC:

60093

AN:

152082

Hom.:

13207

Cov.:

AF XY:

0.387

AC XY:

28797

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.576

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.294

Gnomad4 EAS

AF:

0.0774

Gnomad4 SAS

AF:

0.236

Gnomad4 FIN

AF:

0.354

Gnomad4 NFE

AF:

0.362

Gnomad4 OTH

AF:

0.368

Alfa

AF:

0.370

Hom.:

8647

Bravo

AF:

0.399

Asia WGS

AF:

0.204

AC:

710

AN:

3478

EpiCase

AF:

0.354

EpiControl

AF:

0.362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 58.183% in gnomAD_Exomes) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

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

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.14

DANN

Benign

0.73

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