16-78432512-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016373.4(WWOX):c.816G>T(p.Leu272Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,614,110 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 29 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -1.36

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007000327).

BP6

Variant 16-78432512-G-T is Benign according to our data. Variant chr16-78432512-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241106.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00321 (489/152252) while in subpopulation NFE AF = 0.00557 (379/68016). AF 95% confidence interval is 0.00511. There are 1 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.816G>T	p.Leu272Phe	missense_variant	Exon 8 of 9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2 link	c.477G>T	p.Leu159Phe	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.816G>T	p.Leu272Phe	missense_variant	Exon 8 of 9	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

489

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00432

GnomAD2 exomes

AF:

0.00259

AC:

647

AN:

249400

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.000839

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00461

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00532

AC:

7774

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00517

AC XY:

3762

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00300

AC:

134

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00652

AC:

7255

AN:

1112004

Other (OTH)

AF:

0.00498

AC:

301

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

455

910

1366

1821

2276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.00321

AC:

489

AN:

152252

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41566

American (AMR)

AF:

0.00229

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00557

AC:

379

AN:

68016

Other (OTH)

AF:

0.00427

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00404

Hom.:

Bravo

AF:

0.00336

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00463

AC:

ExAC

AF:

0.00237

AC:

287

EpiCase

AF:

0.00485

EpiControl

AF:

0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 14, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WWOX: BP4, BS2

Nov 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 31, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27527004, 11572989)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

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

not specified

Benign:1

Mar 05, 2021

Genetic Services Laboratory, University of Chicago

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

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0020

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.077

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.46

N;N;.

PhyloP100

-1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.010

N;N;.

REVEL

Benign

0.0

Sift

Benign

0.70

T;T;.

Sift4G

Benign

0.71

T;T;T

Vest4

0.27

ClinPred

0.0051

GERP RS

-12

Varity_R

0.046

gMVP

0.66

Mutation Taster

=91/9

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