rs55664929

Variant names:

• chr12-6012054-C-T
• rs55664929
• NM_000552.5:c.5664+33G>A

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.5664+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 1,610,032 control chromosomes in the GnomAD database, including 1,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (720 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (494 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 2 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=-0.91).
• BP6: Variant 12-6012054-C-T is Benign according to our data. Variant chr12-6012054-C-T is described in ClinVar as Benign. ClinVar VariationId is 256686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.5664+33G>A		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.5664+33G>A		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5664+33G>A		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+17288G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0557 AC: 8469 AN: 152118 Hom.: 721 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.00690 AC: 1715 AN: 248640 AF XY: 0.00534

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00507 AC: 7391 AN: 1457798 Hom.: 494 Cov.: 31 AF XY: 0.00439 AC XY: 3187 AN XY: 725522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.164 AC: 5138 AN: 31278

American (AMR) AF: 0.0113 AC: 505 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 158 AN: 26086

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000615 AC: 53 AN: 86228

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5748

European-Non Finnish (NFE) AF: 0.000694 AC: 771 AN: 1110600

Other (OTH) AF: 0.0114 AC: 687 AN: 60146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0558 AC: 8488 AN: 152234 Hom.: 720 Cov.: 32 AF XY: 0.0533 AC XY: 3971 AN XY: 74452

African (AFR) AF: 0.189 AC: 7821 AN: 41468

American (AMR) AF: 0.0282 AC: 432 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68034

Other (OTH) AF: 0.0516 AC: 109 AN: 2114

Alfa AF: 0.0307 Hom.: 72

Bravo AF: 0.0643

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.46
DANN	Benign	0.27
PhyloP100		-1.7
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: rs55664929; hg19: chr12-6121220;