Genetic Variant VWA8:p.Val1564Met (chr13-41615006-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM5BP4_StrongBP6_ModerateBS2

The NM_015058.2(VWA8):c.4690G>A(p.Val1564Met) variant causes a missense change. The variant allele was found at a frequency of 0.00662 in 1,613,696 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1564L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 38 hom. )

Consequence

VWA8
NM_015058.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.86

Publications

10 publications found

Variant links:

Genes affected

VWA8 (HGNC:29071): (von Willebrand factor A domain containing 8) Predicted to enable ATP binding activity. Located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

VWA8 Gene-Disease associations (from GenCC):

retinitis pigmentosa 97
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

VWA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-41615006-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 617837.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.010855824).

BP6

Variant 13-41615006-C-T is Benign according to our data. Variant chr13-41615006-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2672545.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 694 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015058.2. 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
	VWA8	NM_015058.2	MANE Select	c.4690G>A	p.Val1564Met	missense	Exon 38 of 45	NP_055873.1	A3KMH1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWA8	ENST00000379310.8	TSL:2 MANE Select	c.4690G>A	p.Val1564Met	missense	Exon 38 of 45	ENSP00000368612.3	A3KMH1-1
VWA8	ENST00000938853.1		c.4684G>A	p.Val1562Met	missense	Exon 38 of 45	ENSP00000608912.1
VWA8	ENST00000941315.1		c.4612G>A	p.Val1538Met	missense	Exon 37 of 44	ENSP00000611374.1

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00766

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00456

AC:

1137

AN:

249350

AF XY:

0.00465

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00749

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00684

AC:

9993

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

4839

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33460

American (AMR)

AF:

0.00309

AC:

138

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00269

AC:

232

AN:

86234

European-Finnish (FIN)

AF:

0.00197

AC:

105

AN:

53416

Middle Eastern (MID)

AF:

0.00146

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00822

AC:

9142

AN:

1111936

Other (OTH)

AF:

0.00489

AC:

295

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

513

1027

1540

2054

2567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.00456

AC:

694

AN:

152276

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41546

American (AMR)

AF:

0.00419

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00764

AC:

520

AN:

68032

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00588

Hom.:

Bravo

AF:

0.00431

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00124

AC:

ESP6500EA

AF:

0.00990

AC:

ExAC

AF:

0.00453

AC:

548

EpiCase

AF:

0.00682

EpiControl

AF:

0.00736

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0058

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

PhyloP100

3.9

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

REVEL

Benign

0.15

Sift

Uncertain

0.015

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.69

MVP

0.19

MPC

0.36

ClinPred

0.023

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.66

Mutation Taster

=94/6

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over