rs11063962

Variant names:

• chr12-5967615-G-A
• rs11063962
• NM_000552.5:c.7771-13C>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.7771-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,611,768 control chromosomes in the GnomAD database, including 5,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (298 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5121 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.704
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-5967615-G-A is Benign according to our data. Variant chr12-5967615-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0857 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.7771-13C>T		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.7771-13C>T		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.7771-13C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2968-14021C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8622 AN: 152046 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0561

GnomAD2 exomes AF: 0.0642 AC: 16039 AN: 249854 AF XY: 0.0681

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.0496

Gnomad FIN exome AF: 0.0713

Gnomad NFE exome AF: 0.0778

Gnomad OTH exome AF: 0.0664

GnomAD4 exome AF: 0.0810 AC: 118185 AN: 1459604 Hom.: 5121 Cov.: 32 AF XY: 0.0815 AC XY: 59155 AN XY: 726236

African (AFR) AF: 0.0128 AC: 427 AN: 33464

American (AMR) AF: 0.0324 AC: 1449 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 962 AN: 26134

East Asian (EAS) AF: 0.0514 AC: 2040 AN: 39696

South Asian (SAS) AF: 0.0902 AC: 7783 AN: 86242

European-Finnish (FIN) AF: 0.0692 AC: 3602 AN: 52076

Middle Eastern (MID) AF: 0.0597 AC: 342 AN: 5732

European-Non Finnish (NFE) AF: 0.0874 AC: 97119 AN: 1111194

Other (OTH) AF: 0.0739 AC: 4461 AN: 60346

GnomAD4 genome AF: 0.0566 AC: 8618 AN: 152164 Hom.: 298 Cov.: 32 AF XY: 0.0555 AC XY: 4124 AN XY: 74372

African (AFR) AF: 0.0159 AC: 662 AN: 41528

American (AMR) AF: 0.0488 AC: 746 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.0544 AC: 281 AN: 5170

South Asian (SAS) AF: 0.0929 AC: 447 AN: 4814

European-Finnish (FIN) AF: 0.0643 AC: 682 AN: 10600

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0803 AC: 5458 AN: 67980

Other (OTH) AF: 0.0550 AC: 116 AN: 2108

Alfa AF: 0.0725 Hom.: 623

Bravo AF: 0.0531

Asia WGS AF: 0.0700 AC: 250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 2 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.54
DANN	Benign	0.70
PhyloP100		-0.70
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: rs11063962; hg19: chr12-6076781;