Genetic Variant WWOX:p.Arg156Ser (chr16-78164241-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_016373.4(WWOX):c.468G>T(p.Arg156Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,614,150 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R156R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 7 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.33

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.042405367).

BP6

Variant 16-78164241-G-T is Benign according to our data. Variant chr16-78164241-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 415952.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000689 (105/152318) while in subpopulation EAS AF = 0.00888 (46/5178). AF 95% confidence interval is 0.00684. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WWOX	NM_016373.4	MANE Select	c.468G>T	p.Arg156Ser	missense	Exon 5 of 9	NP_057457.1
WWOX	NM_001291997.2		c.129G>T	p.Arg43Ser	missense	Exon 4 of 8	NP_001278926.1
WWOX	NM_130791.5		c.468G>T	p.Arg156Ser	missense	Exon 5 of 6	NP_570607.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WWOX	ENST00000566780.6	TSL:1 MANE Select	c.468G>T	p.Arg156Ser	missense	Exon 5 of 9	ENSP00000457230.1
WWOX	ENST00000408984.7	TSL:1	c.468G>T	p.Arg156Ser	missense	Exon 5 of 10	ENSP00000386161.3
WWOX	ENST00000406884.6	TSL:1	c.468G>T	p.Arg156Ser	missense	Exon 5 of 6	ENSP00000384495.2

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00118

AC:

294

AN:

249432

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00823

Gnomad FIN exome

AF:

0.00264

Gnomad NFE exome

AF:

0.000645

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000612

AC:

894

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

437

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00650

AC:

258

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00281

AC:

150

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000311

AC:

346

AN:

1111986

Other (OTH)

AF:

0.00215

AC:

130

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152318

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41564

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00888

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68034

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000785

Hom.:

Bravo

AF:

0.000544

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000602

AC:

ExAC

AF:

0.00123

AC:

149

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 05, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Nov 26, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WWOX-related disorder

Benign:1

Aug 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.042

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.6

PhyloP100

3.3

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MutPred

0.86

Loss of MoRF binding (P = 0.0148)

MVP

0.99

ClinPred

0.12

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.84

Mutation Taster

=10/90

disease causing

(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