rs55784921

Variant names:

• chr12-5994572-G-A
• rs55784921
• NM_000552.5:c.6099C>T
• VWF p.Tyr2033Tyr

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000552.5(VWF):​c.6099C>T​(p.Tyr2033Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,613,926 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0890
• Publications: 1 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: Orphanet, ClinGen
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-5994572-G-A is Benign according to our data. Variant chr12-5994572-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.089 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.6099C>T	p.Tyr2033Tyr	synonymous	Exon 36 of 52	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.6099C>T	p.Tyr2033Tyr	synonymous	Exon 36 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.6099C>T	p.Tyr2033Tyr	synonymous	Exon 37 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+34770C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00143 AC: 359 AN: 251202 AF XY: 0.00141

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00224 AC: 3275 AN: 1461670 Hom.: 5 Cov.: 32 AF XY: 0.00217 AC XY: 1578 AN XY: 727142

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.000984 AC: 44 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.000636 AC: 34 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00276 AC: 3074 AN: 1111842

Other (OTH) AF: 0.00176 AC: 106 AN: 60378

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152256 Hom.: 1 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74440

African (AFR) AF: 0.000457 AC: 19 AN: 41542

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00139

EpiCase AF: 0.00213

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.21
PhyloP100		-0.089
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55784921;

hg19: chr12-6103738;