rs12918952

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.535G>A(p.Ala179Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.533 in 1,613,106 control chromosomes in the GnomAD database, including 246,241 homozygotes. In-silico tool predicts 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. A179S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 17197 hom., cov: 32)

Exomes 𝑓: 0.54 ( 229044 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.64

Publications

44 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012559593).

BP6

Variant 16-78386878-G-A is Benign according to our data. Variant chr16-78386878-G-A is described in ClinVar as Benign. ClinVar VariationId is 260740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.535G>A	p.Ala179Thr	missense_variant	Exon 6 of 9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 link	c.196G>A	p.Ala66Thr	missense_variant	Exon 5 of 8		NP_001278926.1	Q9NZC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.535G>A	p.Ala179Thr	missense_variant	Exon 6 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66433

AN:

151856

Hom.:

17201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.0737

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.598

Gnomad OTH

AF:

0.456

GnomAD2 exomes

AF:

0.451

AC:

112445

AN:

249274

AF XY:

0.457

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.491

Gnomad EAS exome

AF:

0.0622

Gnomad FIN exome

AF:

0.584

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.543

AC:

793001

AN:

1461132

Hom.:

229044

Cov.:

AF XY:

0.537

AC XY:

390311

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.175

AC:

5873

AN:

33472

American (AMR)

AF:

0.368

AC:

16455

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.486

AC:

12699

AN:

26130

East Asian (EAS)

AF:

0.0659

AC:

2618

AN:

39698

South Asian (SAS)

AF:

0.275

AC:

23724

AN:

86242

European-Finnish (FIN)

AF:

0.585

AC:

31229

AN:

53390

Middle Eastern (MID)

AF:

0.471

AC:

2718

AN:

5768

European-Non Finnish (NFE)

AF:

0.601

AC:

667681

AN:

1111346

Other (OTH)

AF:

0.497

AC:

30004

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

17378

34757

52135

69514

86892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17648

35296

52944

70592

88240

<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:

0.437

AC:

66430

AN:

151974

Hom.:

17197

Cov.:

AF XY:

0.432

AC XY:

32071

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.197

AC:

8181

AN:

41446

American (AMR)

AF:

0.424

AC:

6480

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1743

AN:

3468

East Asian (EAS)

AF:

0.0740

AC:

383

AN:

5174

South Asian (SAS)

AF:

0.257

AC:

1232

AN:

4796

European-Finnish (FIN)

AF:

0.578

AC:

6091

AN:

10530

Middle Eastern (MID)

AF:

0.517

AC:

151

AN:

292

European-Non Finnish (NFE)

AF:

0.598

AC:

40616

AN:

67970

Other (OTH)

AF:

0.455

AC:

960

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1667

3335

5002

6670

8337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.533

Hom.:

87017

Bravo

AF:

0.417

TwinsUK

AF:

0.596

AC:

2211

ALSPAC

AF:

0.602

AC:

2321

ESP6500AA

AF:

0.195

AC:

757

ESP6500EA

AF:

0.583

AC:

4823

ExAC

AF:

0.450

AC:

54428

Asia WGS

AF:

0.170

AC:

592

AN:

3478

EpiCase

AF:

0.594

EpiControl

AF:

0.595

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 69% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 64. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 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

- -

Apr 20, 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

- -

Malignant tumor of esophagus;C3280452:Autosomal recessive spinocerebellar ataxia 12;C4015519:Developmental and epileptic encephalopathy, 28

Benign:1

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 1

Benign:1

May 28, 2019

Mendelics

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

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.56

N;N

PhyloP100

7.6

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.99

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.53

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.098

B;.

Vest4

0.49

ClinPred

0.011

GERP RS

5.5

Varity_R

0.40

gMVP

0.62

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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