12-6025549-G-A

Variant names:

• chr12-6025549-G-A
• rs73051263
• NM_000552.5:c.3222+31C>T

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.3222+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,485,324 control chromosomes in the GnomAD database, including 42,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6822 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35204 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.05
• Publications: 2 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=-0.89).
• BP6: Variant 12-6025549-G-A is Benign according to our data. Variant chr12-6025549-G-A is described in ClinVar as Benign. ClinVar VariationId is 256662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 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.3222+31C>T		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.3222+31C>T		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-31615C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42827 AN: 151868 Hom.: 6809 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.203 AC: 48777 AN: 240486 AF XY: 0.197

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.000440

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.223 AC: 297209 AN: 1333338 Hom.: 35204 Cov.: 21 AF XY: 0.220 AC XY: 146985 AN XY: 668846

African (AFR) AF: 0.418 AC: 12500 AN: 29918

American (AMR) AF: 0.134 AC: 5841 AN: 43744

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 5995 AN: 25230

East Asian (EAS) AF: 0.000305 AC: 12 AN: 39378

South Asian (SAS) AF: 0.114 AC: 9476 AN: 83222

European-Finnish (FIN) AF: 0.248 AC: 13086 AN: 52774

Middle Eastern (MID) AF: 0.185 AC: 919 AN: 4960

European-Non Finnish (NFE) AF: 0.237 AC: 236628 AN: 997872

Other (OTH) AF: 0.227 AC: 12752 AN: 56240

GnomAD4 genome AF: 0.282 AC: 42881 AN: 151986 Hom.: 6822 Cov.: 32 AF XY: 0.274 AC XY: 20396 AN XY: 74312

African (AFR) AF: 0.424 AC: 17540 AN: 41416

American (AMR) AF: 0.208 AC: 3184 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 831 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5174

South Asian (SAS) AF: 0.110 AC: 527 AN: 4802

European-Finnish (FIN) AF: 0.249 AC: 2629 AN: 10574

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17338 AN: 67950

Other (OTH) AF: 0.261 AC: 549 AN: 2106

Alfa AF: 0.268 Hom.: 1068

Bravo AF: 0.288

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 11, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.89
CADD	Benign	0.046
DANN	Benign	0.52
PhyloP100		-4.1
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: rs73051263; hg19: chr12-6134715; COSMIC: COSV54615946; COSMIC: COSV54615946;