NM_000552.5:c.2282-42C>A

Variant names:

• chr12-6044493-G-T
• rs216293
• NM_000552.5:c.2282-42C>A

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.2282-42C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,601,648 control chromosomes in the GnomAD database, including 240,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20148 hom., cov: 32)
  • Exomes 𝑓: 0.55 (220604 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.420
• Publications: 22 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=-0.84).
• BP6: Variant 12-6044493-G-T is Benign according to our data. Variant chr12-6044493-G-T is described in ClinVar as Benign. ClinVar VariationId is 256658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.2282-42C>A		intron	N/A	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.2282-42C>A		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-50559C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74953 AN: 151954 Hom.: 20135 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.585 AC: 135035 AN: 230794 AF XY: 0.586

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.722

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.547 AC: 793387 AN: 1449576 Hom.: 220604 Cov.: 35 AF XY: 0.550 AC XY: 396376 AN XY: 720474

African (AFR) AF: 0.276 AC: 9149 AN: 33188

American (AMR) AF: 0.723 AC: 31229 AN: 43174

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 16836 AN: 25932

East Asian (EAS) AF: 0.699 AC: 27398 AN: 39222

South Asian (SAS) AF: 0.629 AC: 53433 AN: 84950

European-Finnish (FIN) AF: 0.525 AC: 27306 AN: 51984

Middle Eastern (MID) AF: 0.649 AC: 3680 AN: 5674

European-Non Finnish (NFE) AF: 0.535 AC: 591373 AN: 1105520

Other (OTH) AF: 0.550 AC: 32983 AN: 59932

GnomAD4 genome AF: 0.493 AC: 74994 AN: 152072 Hom.: 20148 Cov.: 32 AF XY: 0.501 AC XY: 37251 AN XY: 74320

African (AFR) AF: 0.283 AC: 11735 AN: 41496

American (AMR) AF: 0.646 AC: 9880 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2230 AN: 3468

East Asian (EAS) AF: 0.705 AC: 3623 AN: 5142

South Asian (SAS) AF: 0.654 AC: 3149 AN: 4816

European-Finnish (FIN) AF: 0.537 AC: 5684 AN: 10584

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36871 AN: 67956

Other (OTH) AF: 0.538 AC: 1135 AN: 2110

Alfa AF: 0.513 Hom.: 29005

Bravo AF: 0.491

Asia WGS AF: 0.640 AC: 2226 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.59
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs216293; hg19: chr12-6153659;