rs61750601

chr12-6016744-G-Achr12-6016744-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 id is 100418.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Likely_benign=2, Benign=2}. Variant chr12-6016744-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 595 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.5170+10C>T		intron_variant		ENST00000261405.10
VWF	XM_047429501.1	c.5170+10C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.5170+10C>T		intron_variant		1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-22810C>T		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.00403 AC: 1014 AN: 251476 Hom.: 4 AF XY: 0.00405 AC XY: 551 AN XY: 135912

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 SAS exome AF: 0.00127

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

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00666

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00392

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00352 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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2022	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) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 15, 2021	- -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 28, 2023

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

Likely benign, no assertion criteria provided

clinical testing

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

Nov 01, 2020

ClinGen Pathogenicity Calculator -

von Willebrand disease type 1 Benign:1

Likely benign, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Dec 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	19
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs61750601; hg19: chr12-6125910;