12-6077501-A-G

Variant names:

• chr12-6077501-A-G
• rs2239153
• NM_000552.5:c.658-1950T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000552.5(VWF):​c.658-1950T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 151,700 control chromosomes in the GnomAD database, including 23,134 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.53 (23134 hom., cov: 33)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 7 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.73 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.658-1950T>C		intron	N/A	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.658-1950T>C		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.658-1950T>C		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.658-1950T>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81084 AN: 151582 Hom.: 23103 Cov.: 33

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.507

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.535 AC: 81149 AN: 151700 Hom.: 23134 Cov.: 33 AF XY: 0.529 AC XY: 39256 AN XY: 74140

African (AFR) AF: 0.737 AC: 30472 AN: 41328

American (AMR) AF: 0.407 AC: 6215 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1815 AN: 3462

East Asian (EAS) AF: 0.377 AC: 1940 AN: 5150

South Asian (SAS) AF: 0.431 AC: 2078 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4696 AN: 10532

Middle Eastern (MID) AF: 0.503 AC: 146 AN: 290

European-Non Finnish (NFE) AF: 0.476 AC: 32260 AN: 67830

Other (OTH) AF: 0.502 AC: 1058 AN: 2108

Alfa AF: 0.495 Hom.: 2696

Bravo AF: 0.547

Asia WGS AF: 0.368 AC: 1281 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.23
PhyloP100		0.23
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2239153;

hg19: chr12-6186667;