Genetic Variant NM_000552.5:c.6798+14C>T (chr12-5991805-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000552.5(VWF):c.6798+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,308 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 198 hom., cov: 33)

Exomes 𝑓: 0.013 ( 346 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.173

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=-0.81).

BP6

Variant 12-5991805-G-A is Benign according to our data. Variant chr12-5991805-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5991805-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.6798+14C>T		intron_variant	Intron 38 of 51	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.6798+14C>T		intron_variant	Intron 38 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.6798+14C>T		intron_variant	Intron 38 of 51	1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4928

AN:

152172

Hom.:

197

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0193

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00820

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0187

AC:

4694

AN:

251040

Hom.:

127

AF XY:

0.0193

AC XY:

2616

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.0880

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0246

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0487

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0127

AC:

18579

AN:

1461018

Hom.:

346

Cov.:

AF XY:

0.0138

AC XY:

10031

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.0933

Gnomad4 AMR exome

AF:

0.0138

Gnomad4 ASJ exome

AF:

0.0243

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0482

Gnomad4 FIN exome

AF:

0.00127

Gnomad4 NFE exome

AF:

0.00791

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.0324

AC:

4936

AN:

152290

Hom.:

198

Cov.:

AF XY:

0.0318

AC XY:

2369

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0893

Gnomad4 AMR

AF:

0.0193

Gnomad4 ASJ

AF:

0.0279

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0424

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00820

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.0226

Hom.:

Bravo

AF:

0.0353

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

von Willebrand disease type 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

von Willebrand disease type 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.2

DANN

Benign

0.21

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