12-5996852-T-C

Variant names:

• chr12-5996852-T-C
• rs216904
• NM_000552.5:c.5843-630A>G

Variant summary

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

The NM_000552.5(VWF):​c.5843-630A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 151,850 control chromosomes in the GnomAD database, including 12,017 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 0.39 (12017 hom., cov: 30)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 16 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: ClinGen, Orphanet
• 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 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.5843-630A>G		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.5843-630A>G		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5843-630A>G		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+32490A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58687 AN: 151734 Hom.: 11994 Cov.: 30

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.387 AC: 58751 AN: 151850 Hom.: 12017 Cov.: 30 AF XY: 0.395 AC XY: 29278 AN XY: 74186

African (AFR) AF: 0.313 AC: 12956 AN: 41354

American (AMR) AF: 0.449 AC: 6863 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1193 AN: 3468

East Asian (EAS) AF: 0.748 AC: 3869 AN: 5170

South Asian (SAS) AF: 0.532 AC: 2560 AN: 4816

European-Finnish (FIN) AF: 0.396 AC: 4172 AN: 10528

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25855 AN: 67930

Other (OTH) AF: 0.386 AC: 812 AN: 2102

Alfa AF: 0.390 Hom.: 8107

Bravo AF: 0.385

Asia WGS AF: 0.583 AC: 2026 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.42
PhyloP100		-1.0
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: rs216904; hg19: chr12-6106018;