12-6034818-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BA1

The NM_000552.5(VWF):c.2555A>G(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 1,614,050 control chromosomes in the GnomAD database, including 662,737 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q852E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.92 ( 64098 hom., cov: 33)

Exomes 𝑓: 0.90 ( 598639 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.552

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000552.5

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.

BP4

Computational evidence support a benign effect (MetaRNN=5.94502E-7).

BP6

Variant 12-6034818-T-C is Benign according to our data. Variant chr12-6034818-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2555A>G	p.Gln852Arg	missense_variant	Exon 20 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-40884A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.917

AC:

139460

AN:

152158

Hom.:

64045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.923

Gnomad AMR

AF:

0.922

Gnomad ASJ

AF:

0.941

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.876

Gnomad FIN

AF:

0.897

Gnomad MID

AF:

0.917

Gnomad NFE

AF:

0.908

Gnomad OTH

AF:

0.924

GnomAD2 exomes

AF:

0.900

AC:

226185

AN:

251332

AF XY:

0.898

show subpopulations

Gnomad AFR exome

AF:

0.951

Gnomad AMR exome

AF:

0.917

Gnomad ASJ exome

AF:

0.945

Gnomad EAS exome

AF:

0.794

Gnomad FIN exome

AF:

0.895

Gnomad NFE exome

AF:

0.908

Gnomad OTH exome

AF:

0.909

GnomAD4 exome

AF:

0.905

AC:

1322288

AN:

1461774

Hom.:

598639

Cov.:

AF XY:

0.903

AC XY:

656815

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.954

AC:

31945

AN:

33476

Gnomad4 AMR exome

AF:

0.916

AC:

40966

AN:

44720

Gnomad4 ASJ exome

AF:

0.945

AC:

24700

AN:

26136

Gnomad4 EAS exome

AF:

0.795

AC:

31553

AN:

39694

Gnomad4 SAS exome

AF:

0.869

AC:

74934

AN:

86248

Gnomad4 FIN exome

AF:

0.888

AC:

47455

AN:

53418

Gnomad4 NFE exome

AF:

0.909

AC:

1010614

AN:

1111926

Gnomad4 Remaining exome

AF:

0.908

AC:

54803

AN:

60388

Heterozygous variant carriers

7213

14427

21640

28854

36067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

21484

42968

64452

85936

107420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.917

AC:

139570

AN:

152276

Hom.:

64098

Cov.:

AF XY:

0.915

AC XY:

68148

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.951

AC:

0.950888

AN:

0.950888

Gnomad4 AMR

AF:

0.922

AC:

0.921861

AN:

0.921861

Gnomad4 ASJ

AF:

0.941

AC:

0.940668

AN:

0.940668

Gnomad4 EAS

AF:

0.792

AC:

0.792037

AN:

0.792037

Gnomad4 SAS

AF:

0.877

AC:

0.877127

AN:

0.877127

Gnomad4 FIN

AF:

0.897

AC:

0.897078

AN:

0.897078

Gnomad4 NFE

AF:

0.908

AC:

0.908294

AN:

0.908294

Gnomad4 OTH

AF:

0.919

AC:

0.918561

AN:

0.918561

Heterozygous variant carriers

593

1186

1778

2371

2964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.910

Hom.:

289495

Bravo

AF:

0.921

ESP6500AA

AF:

0.950

AC:

4184

ESP6500EA

AF:

0.911

AC:

7832

ExAC

AF:

0.899

AC:

109150

Asia WGS

AF:

0.840

AC:

2924

AN:

3478

EpiCase

AF:

0.914

EpiControl

AF:

0.918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.9

DANN

Benign

0.54

DEOGEN2

Benign

0.30

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.010

MetaRNN

Benign

5.9e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.42

PrimateAI

Benign

0.25

PROVEAN

Benign

1.3

REVEL

Benign

0.086

Sift

Benign

1.0

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.037

MPC

0.20

ClinPred

0.00065

GERP RS

0.42

Varity_R

0.045

gMVP

0.38

Mutation Taster

=98/2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over