rs61749367

chr12-6019732-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000552.5(VWF):c.3686T>G(p.Val1229Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,610,354 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1229I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 3.55

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a strand (size 7) in uniprot entity VWF_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0033665001).
• BP6: Variant 12-6019732-A-C is Benign according to our data. Variant chr12-6019732-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100274.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, not_provided=1, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00641 (977/152324) while in subpopulation AFR AF= 0.0179 (744/41566). AF 95% confidence interval is 0.0168. There are 6 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 971 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.3686T>G	p.Val1229Gly	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.3686T>G	p.Val1229Gly	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.3686T>G	p.Val1229Gly	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000539641.1	n.484T>G		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5	n.421-25798T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152206 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00157 AC: 380 AN: 241848 Hom.: 2 AF XY: 0.00158 AC XY: 208 AN XY: 131946

Gnomad AFR exome AF: 0.00983

Gnomad AMR exome AF: 0.000702

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.00298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000855

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00180 AC: 2626 AN: 1458030 Hom.: 11 Cov.: 38 AF XY: 0.00196 AC XY: 1421 AN XY: 725198

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00641 AC: 977 AN: 152324 Hom.: 6 Cov.: 32 AF XY: 0.00608 AC XY: 453 AN XY: 74492

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00571 Hom.: 1

Bravo AF: 0.00703

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00204 AC: 247

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2017	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

von Willebrand disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

von Willebrand disease type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

Abnormality of coagulation Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

von Willebrand disease type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Benign	0.35
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.020	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.0	N
MutationTaster	Benign	0.81	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.37
MPC		0.35
ClinPred		0.0028	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749367; hg19: chr12-6128898; COSMIC: COSV54633722;