NM_000552.5:c.2967+1594T>C

Variant names:

• chr12-6027748-A-G
• rs216315
• NM_000552.5:c.2967+1594T>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.2967+1594T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 151,954 control chromosomes in the GnomAD database, including 64,544 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.

• Frequency: Genomes: 𝑓 0.92 (64544 hom., cov: 29)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.955 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.2967+1594T>C		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.2967+1594T>C		intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-33814T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.921 AC: 139794 AN: 151836 Hom.: 64489 Cov.: 29

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.926

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.909

Gnomad OTH AF: 0.931

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

GnomAD4 genome AF: 0.921 AC: 139906 AN: 151954 Hom.: 64544 Cov.: 29 AF XY: 0.919 AC XY: 68281 AN XY: 74262

African (AFR) AF: 0.963 AC: 39900 AN: 41432

American (AMR) AF: 0.926 AC: 14152 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3268 AN: 3472

East Asian (EAS) AF: 0.797 AC: 4096 AN: 5142

South Asian (SAS) AF: 0.878 AC: 4215 AN: 4802

European-Finnish (FIN) AF: 0.897 AC: 9451 AN: 10542

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.909 AC: 61760 AN: 67974

Other (OTH) AF: 0.926 AC: 1950 AN: 2106

Alfa AF: 0.909 Hom.: 9931

Bravo AF: 0.926

Asia WGS AF: 0.845 AC: 2939 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.47
PhyloP100		-0.44
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: rs216315; hg19: chr12-6136914;