rs177702

Variant names:

• chr12-5985679-G-A
• rs177702
• NM_000552.5:c.6799-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-5985679-G-A
• chr12-5985679-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.6799-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 1,612,346 control chromosomes in the GnomAD database, including 500,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43962 hom., cov: 33)
  • Exomes 𝑓: 0.79 (456519 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.05
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-5985679-G-A is Benign according to our data. Variant chr12-5985679-G-A is described in ClinVar as Benign. ClinVar VariationId is 256693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.6799-14C>T		intron_variant	Intron 38 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6799-14C>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	c.6799-14C>T		intron_variant	Intron 38 of 51	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115204 AN: 152080 Hom.: 43924 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.779 AC: 194353 AN: 249600 AF XY: 0.774

Gnomad AFR exome AF: 0.671

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.821

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.785

GnomAD4 exome AF: 0.789 AC: 1152384 AN: 1460148 Hom.: 456519 Cov.: 39 AF XY: 0.786 AC XY: 570996 AN XY: 726442

African (AFR) AF: 0.658 AC: 22015 AN: 33444

American (AMR) AF: 0.867 AC: 38758 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 21475 AN: 26126

East Asian (EAS) AF: 0.729 AC: 28915 AN: 39676

South Asian (SAS) AF: 0.682 AC: 58802 AN: 86184

European-Finnish (FIN) AF: 0.800 AC: 42531 AN: 53174

Middle Eastern (MID) AF: 0.731 AC: 4210 AN: 5762

European-Non Finnish (NFE) AF: 0.800 AC: 889133 AN: 1110754

Other (OTH) AF: 0.771 AC: 46545 AN: 60336

GnomAD4 genome AF: 0.758 AC: 115297 AN: 152198 Hom.: 43962 Cov.: 33 AF XY: 0.756 AC XY: 56263 AN XY: 74392

African (AFR) AF: 0.673 AC: 27937 AN: 41524

American (AMR) AF: 0.812 AC: 12418 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2865 AN: 3468

East Asian (EAS) AF: 0.674 AC: 3476 AN: 5160

South Asian (SAS) AF: 0.671 AC: 3241 AN: 4830

European-Finnish (FIN) AF: 0.793 AC: 8401 AN: 10588

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54427 AN: 68010

Other (OTH) AF: 0.772 AC: 1630 AN: 2112

Alfa AF: 0.774 Hom.: 9182

Bravo AF: 0.759

Asia WGS AF: 0.696 AC: 2422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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: 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 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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	-0.87
CADD	Benign	0.11
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs177702; hg19: chr12-6094845;