NM_016373.4:c.844C>G

Variant names:

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.844C>G(p.Pro282Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,098 control chromosomes in the GnomAD database, including 3,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P282L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.074 ( 476 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2915 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.57

Publications

39 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=0.0044485033).

BP6

Variant 16-78432540-C-G is Benign according to our data. Variant chr16-78432540-C-G is described in ClinVar as Benign. ClinVar VariationId is 260745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.844C>G	p.Pro282Ala	missense	Exon 8 of 9	NP_057457.1
	WWOX	NM_001291997.2		c.505C>G	p.Pro169Ala	missense	Exon 7 of 8	NP_001278926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.844C>G	p.Pro282Ala	missense	Exon 8 of 9	ENSP00000457230.1
WWOX	ENST00000408984.7	TSL:1	c.844C>G	p.Pro282Ala	missense	Exon 8 of 10	ENSP00000386161.3
WWOX	ENST00000402655.6	TSL:1	c.409+317386C>G		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes

AF:

0.0735

AC:

11184

AN:

152100

Hom.:

477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0959

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0796

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.0916

Gnomad SAS

AF:

0.0919

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0575

Gnomad OTH

AF:

0.0686

GnomAD2 exomes

AF:

0.0711

AC:

17732

AN:

249482

AF XY:

0.0707

show subpopulations

Gnomad AFR exome

AF:

0.0943

Gnomad AMR exome

AF:

0.0797

Gnomad ASJ exome

AF:

0.0980

Gnomad EAS exome

AF:

0.0867

Gnomad FIN exome

AF:

0.0560

Gnomad NFE exome

AF:

0.0583

Gnomad OTH exome

AF:

0.0710

GnomAD4 exome

AF:

0.0595

AC:

87031

AN:

1461880

Hom.:

2915

Cov.:

AF XY:

0.0601

AC XY:

43702

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.100

AC:

3357

AN:

33480

American (AMR)

AF:

0.0797

AC:

3564

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0987

AC:

2579

AN:

26136

East Asian (EAS)

AF:

0.0814

AC:

3233

AN:

39700

South Asian (SAS)

AF:

0.0875

AC:

7549

AN:

86256

European-Finnish (FIN)

AF:

0.0610

AC:

3260

AN:

53420

Middle Eastern (MID)

AF:

0.0669

AC:

386

AN:

5768

European-Non Finnish (NFE)

AF:

0.0532

AC:

59208

AN:

1112000

Other (OTH)

AF:

0.0645

AC:

3895

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

5166

10332

15499

20665

25831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2274

4548

6822

9096

11370

<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:

0.0736

AC:

11203

AN:

152218

Hom.:

476

Cov.:

AF XY:

0.0739

AC XY:

5500

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0960

AC:

3987

AN:

41542

American (AMR)

AF:

0.0800

AC:

1222

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3472

East Asian (EAS)

AF:

0.0916

AC:

474

AN:

5172

South Asian (SAS)

AF:

0.0918

AC:

442

AN:

4814

European-Finnish (FIN)

AF:

0.0540

AC:

573

AN:

10602

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0575

AC:

3913

AN:

68020

Other (OTH)

AF:

0.0683

AC:

144

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

536

1072

1607

2143

2679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0611

Hom.:

241

Bravo

AF:

0.0721

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0503

AC:

194

ESP6500AA

AF:

0.0865

AC:

340

ESP6500EA

AF:

0.0592

AC:

491

ExAC

AF:

0.0743

AC:

8977

Asia WGS

AF:

0.0890

AC:

312

AN:

3478

EpiCase

AF:

0.0547

EpiControl

AF:

0.0549

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 05, 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.

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.2

PhyloP100

7.6

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.43

Sift

Benign

0.066

Sift4G

Benign

0.54

Polyphen

0.99

Vest4

0.42

ClinPred

0.045

GERP RS

5.9

Varity_R

0.22

gMVP

0.78

Mutation Taster

=4/96

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over