chr12-5977099-T-C

Variant names:

• chr12-5977099-T-C
• rs216856
• NM_000552.5:c.7288-839A>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.7288-839A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 152,096 control chromosomes in the GnomAD database, including 28,433 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 0.60 (28433 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 12 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.7288-839A>G		intron_variant	Intron 42 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.7288-839A>G		intron_variant	Intron 42 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.7288-839A>G		intron_variant	Intron 42 of 51	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91779 AN: 151978 Hom.: 28403 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.626

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

GnomAD4 genome AF: 0.604 AC: 91851 AN: 152096 Hom.: 28433 Cov.: 32 AF XY: 0.608 AC XY: 45180 AN XY: 74324

African (AFR) AF: 0.459 AC: 19061 AN: 41486

American (AMR) AF: 0.686 AC: 10498 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2387 AN: 3472

East Asian (EAS) AF: 0.666 AC: 3445 AN: 5170

South Asian (SAS) AF: 0.608 AC: 2922 AN: 4808

European-Finnish (FIN) AF: 0.688 AC: 7270 AN: 10560

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44155 AN: 67986

Other (OTH) AF: 0.628 AC: 1327 AN: 2112

Alfa AF: 0.639 Hom.: 18074

Bravo AF: 0.602

Asia WGS AF: 0.646 AC: 2244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.69
PhyloP100		-1.4
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: rs216856; hg19: chr12-6086265;