chr12-6057850-C-A

Variant names:

• chr12-6057850-C-A
• rs150146744
• NM_000552.5:c.1728G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.1728G>T is a missense variant in VWF that replaces methionine with isoleucine at position 576. The The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02820 (based on 1745/59454 alleles in the Admixed American population, with 41 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in the heterozygous state in at least 6 patients with a diagnosed blood disorder, with several exhibiting mild or moderate reduction of VWF:Ag (PMID:17190853, PMID:25780857, PMID:33556167). However, diagnoses are not consistent and the variant is ineligible for consideration for PS4 due to its high frequency in the control population. The computational predictor REVEL gives a score of 0.038, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228284/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0016 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: VWF NM_000552.5 missense, splice_region
• Scores: Splicing: ADA: 0.03487
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:7 O:1
• Conservation: PhyloP100: 1.52
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.1728G>T	p.Met576Ile	missense splice_region	Exon 14 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.1728G>T	p.Met576Ile	missense splice_region	Exon 14 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.1728G>T	p.Met576Ile	missense splice_region	Exon 15 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.1728G>T	p.Met576Ile	missense splice_region	Exon 14 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152202 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00546 AC: 1332 AN: 243966 AF XY: 0.00410

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00434

GnomAD4 exome AF: 0.00117 AC: 1707 AN: 1454016 Hom.: 38 Cov.: 30 AF XY: 0.00101 AC XY: 731 AN XY: 722530

African (AFR) AF: 0.000150 AC: 5 AN: 33280

American (AMR) AF: 0.0349 AC: 1540 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25706

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39606

South Asian (SAS) AF: 0.000223 AC: 19 AN: 85368

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52266

Middle Eastern (MID) AF: 0.000368 AC: 2 AN: 5434

European-Non Finnish (NFE) AF: 0.0000830 AC: 92 AN: 1108136

Other (OTH) AF: 0.000699 AC: 42 AN: 60076

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152320 Hom.: 3 Cov.: 31 AF XY: 0.00162 AC XY: 121 AN XY: 74484

African (AFR) AF: 0.000289 AC: 12 AN: 41572

American (AMR) AF: 0.0134 AC: 205 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000696 Hom.: 3

Bravo AF: 0.00307

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00443 AC: 537

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (6)
-	-	2	Hereditary von Willebrand disease (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.038
Sift	Benign	0.065	T
Sift4G	Benign	0.28	T
Polyphen		0.0060	B
Vest4		0.14
MutPred		0.37		Gain of catalytic residue at N573 (P = 0.0015)
MVP		0.44
MPC		0.21
ClinPred		0.016	T
GERP RS		1.4
Varity_R		0.20
gMVP		0.42
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.035
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.080		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: rs150146744; hg19: chr12-6167016;