12-6016744-G-A

Variant names:

• chr12-6016744-G-A
• rs61750601
• NM_000552.5:c.5170+10C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6 BS2_Supporting

The NM_000552.5(VWF):​c.5170+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,122 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5 O:1
• Conservation: PhyloP100: -2.86
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 12-6016744-G-A is Benign according to our data. Variant chr12-6016744-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100418.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.5170+10C>T		intron_variant	Intron 29 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5170+10C>T		intron_variant	Intron 29 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5170+10C>T		intron_variant	Intron 29 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-22810C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00403 AC: 1014 AN: 251476 AF XY: 0.00405

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00433 AC: 6326 AN: 1461824 Hom.: 24 Cov.: 32 AF XY: 0.00429 AC XY: 3118 AN XY: 727220

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00302 AC: 135 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 174 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00112 AC: 97 AN: 86252

European-Finnish (FIN) AF: 0.0120 AC: 641 AN: 53420

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5756

European-Non Finnish (NFE) AF: 0.00449 AC: 4995 AN: 1111964

Other (OTH) AF: 0.00392 AC: 237 AN: 60394

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74466

African (AFR) AF: 0.00123 AC: 51 AN: 41556

American (AMR) AF: 0.00379 AC: 58 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00329 Hom.: 2

Bravo AF: 0.00331

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2 Other:1

Sep 22, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in patients with features of von Willebrand disease in published literature, however, the variant was seen with other VWF variant(s) on the same allele and/or another VWF variant on the opposite allele (in trans) in most cases (Baronciani et al., 2003; Fidalgo et al., 2016; Borras et al., 2017); Observed in heterozygous state in patients with von Willebrand disease type 1, however, the variant was also observed in unaffected family members (Cumming et al., 2006; Goodeve et al., 2007); Observed in the homozygous state in a patient with features of von Willebrand disease type 3, however, this patient was also homozygous for another splice variant in the VWF gene that may have contributed to the phenotype (Corrales et al., 2011); Studies of mRNA from patient leukocytes suggest normal mRNA processing, however additional studies are needed to validate the functional effect of this variant (Corrales et al., 2011); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 16985174, 26988807, 11057846, 28971901, 34426522, 17080221, 21251206, 12737944, 33550700) -

Oct 15, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Nov 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VWF c.5170+10C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. Consistently, functional studies evaluating an impact on splicing have identified no visible splicing impact in leukocytes and platelets (example, Corrales_2011). The variant allele was found at a frequency of 0.004 in 251476 control chromosomes in the gnomAD database, including 4 homozygotes. c.5170+10C>T has been reported in the literature as a compound heterozygous and compound homozygous genotype in individuals affected with Von Willebrand Disease type I, type 1H and type 3 (example, Baronciani_2000, Borras_2017, Ornaghi_2021), without strong evidence for causality. These data do not allow any conclusion about variant significance. Multiple reports of co-occurrences with another pathogenic variant in cis have been reported (VWF c.7730-1G>C, Borras_2017, Corrales_2011), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 11057846, 28971901, 21251206, 33550700). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=3; Benign/Likely benign, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

von Willebrand disease type 3 Benign:1

Nov 01, 2020

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

ClinGen Pathogenicity Calculator -

von Willebrand disease type 1 Benign:1

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	19
DANN	Benign	0.71
PhyloP100		-2.9
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61750601; hg19: chr12-6125910;