NM_016373.4:c.293C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016373.4(WWOX):c.293C>T(p.Pro98Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0141 in 1,614,118 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P98P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.014 ( 169 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.09

Publications

14 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=0.0043513775).

BP6

Variant 16-78115038-C-T is Benign according to our data. Variant chr16-78115038-C-T is described in ClinVar as Benign. ClinVar VariationId is 241101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0143 (2179/152236) while in subpopulation AMR AF = 0.0171 (261/15284). AF 95% confidence interval is 0.0154. There are 23 homozygotes in GnomAd4. There are 1001 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.293C>T	p.Pro98Leu	missense_variant	Exon 4 of 9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.293C>T	p.Pro98Leu	missense_variant	Exon 4 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2177

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00376

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0123

AC:

3075

AN:

249570

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0341

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00431

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0141

AC:

20542

AN:

1461882

Hom.:

169

Cov.:

AF XY:

0.0138

AC XY:

10020

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0147

AC:

493

AN:

33480

American (AMR)

AF:

0.0123

AC:

551

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

913

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00555

AC:

479

AN:

86258

European-Finnish (FIN)

AF:

0.00461

AC:

246

AN:

53418

Middle Eastern (MID)

AF:

0.0231

AC:

133

AN:

5768

European-Non Finnish (NFE)

AF:

0.0151

AC:

16790

AN:

1112002

Other (OTH)

AF:

0.0154

AC:

933

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1246

2492

3737

4983

6229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.0143

AC:

2179

AN:

152236

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

1001

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0164

AC:

680

AN:

41522

American (AMR)

AF:

0.0171

AC:

261

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

113

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00456

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0149

AC:

1011

AN:

68020

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0148

Hom.:

Bravo

AF:

0.0160

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.0173

AC:

ESP6500EA

AF:

0.0144

AC:

118

ExAC

AF:

0.0112

AC:

1359

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 12, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 27, 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 03, 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

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;T;.;.

Eigen

Benign

0.077

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.74

T;T;T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;L;L;.;L;L

PhyloP100

4.1

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;D;D;D;D;D

REVEL

Benign

0.16

Sift

Benign

0.044

D;D;D;D;D;D

Sift4G

Benign

0.091

T;D;D;D;D;T

Polyphen

0.60

P;B;P;.;B;.

Vest4

0.70

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.47

Mutation Taster

=97/3

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over