rs2270151

Variant names:

• chr12-5951794-G-A
• rs2270151
• NM_000552.5:c.8155+50C>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.8155+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,602,898 control chromosomes in the GnomAD database, including 18,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1352 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16974 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.327
• Publications: 17 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=-0.9).
• BP6: Variant 12-5951794-G-A is Benign according to our data. Variant chr12-5951794-G-A is described in ClinVar as Benign. ClinVar VariationId is 256704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.167 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.8155+50C>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.8155+50C>T		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.8155+50C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.3235+50C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18992 AN: 152106 Hom.: 1352 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.134 AC: 33804 AN: 251340 AF XY: 0.136

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.0781

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.149 AC: 216698 AN: 1450674 Hom.: 16974 Cov.: 29 AF XY: 0.149 AC XY: 107294 AN XY: 722370

African (AFR) AF: 0.0692 AC: 2299 AN: 33240

American (AMR) AF: 0.0817 AC: 3653 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5351 AN: 26048

East Asian (EAS) AF: 0.169 AC: 6687 AN: 39642

South Asian (SAS) AF: 0.105 AC: 9027 AN: 86034

European-Finnish (FIN) AF: 0.117 AC: 6258 AN: 53392

Middle Eastern (MID) AF: 0.162 AC: 931 AN: 5752

European-Non Finnish (NFE) AF: 0.157 AC: 173089 AN: 1101858

Other (OTH) AF: 0.157 AC: 9403 AN: 60002

GnomAD4 genome AF: 0.125 AC: 18997 AN: 152224 Hom.: 1352 Cov.: 32 AF XY: 0.123 AC XY: 9156 AN XY: 74432

African (AFR) AF: 0.0704 AC: 2927 AN: 41550

American (AMR) AF: 0.116 AC: 1770 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3470

East Asian (EAS) AF: 0.176 AC: 911 AN: 5176

South Asian (SAS) AF: 0.100 AC: 482 AN: 4816

European-Finnish (FIN) AF: 0.111 AC: 1178 AN: 10610

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10491 AN: 67994

Other (OTH) AF: 0.143 AC: 302 AN: 2112

Alfa AF: 0.150 Hom.: 3151

Bravo AF: 0.126

Asia WGS AF: 0.158 AC: 549 AN: 3478

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	-0.90
CADD	Benign	2.0
DANN	Benign	0.47
PhyloP100		0.33
Mutation Taster		=99/1	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: rs2270151; hg19: chr12-6060960; COSMIC: COSV54611921; COSMIC: COSV54611921;