rs73572838

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.941G>A(p.Arg314His) variant causes a missense change. The variant allele was found at a frequency of 0.00616 in 1,614,114 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.031 ( 222 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 227 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.22

Publications

16 publications found

Variant links:

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WWOX Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive spinocerebellar ataxia 12
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WWOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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, 23 uncertain in NM_016373.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0026435852).

BP6

Variant 16-78432637-G-A is Benign according to our data. Variant chr16-78432637-G-A is described in ClinVar as Benign. ClinVar VariationId is 260746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.941G>A	p.Arg314His	missense_variant	Exon 8 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2 link	c.602G>A	p.Arg201His	missense_variant	Exon 7 of 8		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.941G>A	p.Arg314His	missense_variant	Exon 8 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4715

AN:

152106

Hom.:

220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.00797

AC:

1989

AN:

249576

AF XY:

0.00592

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.00446

Gnomad ASJ exome

AF:

0.00913

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000477

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00356

AC:

5201

AN:

1461890

Hom.:

227

Cov.:

AF XY:

0.00312

AC XY:

2268

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.115

AC:

3839

AN:

33480

American (AMR)

AF:

0.00494

AC:

221

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00968

AC:

253

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000278

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000235

AC:

261

AN:

1112010

Other (OTH)

AF:

0.00931

AC:

562

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

340

680

1019

1359

1699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0311

AC:

4738

AN:

152224

Hom.:

222

Cov.:

AF XY:

0.0303

AC XY:

2258

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.107

AC:

4449

AN:

41510

American (AMR)

AF:

0.0115

AC:

176

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68020

Other (OTH)

AF:

0.0237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

217

434

651

868

1085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0113

Hom.:

159

Bravo

AF:

0.0351

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0960

AC:

396

ESP6500EA

AF:

0.000833

AC:

ExAC

AF:

0.00975

AC:

1180

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 07, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 12

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.075

T;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

L;L;.

PhyloP100

5.2

PrimateAI

Benign

0.30

PROVEAN

Benign

0.0

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.71

T;T;.

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0050

B;.;.

Vest4

0.27

MVP

0.86

ClinPred

0.011

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.73

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over