chr16-78425018-C-G

Position:

chr16-78425018-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.754C>G(p.Pro252Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00893 in 1,614,016 control chromosomes in the GnomAD database, including 562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 57 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 505 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 5.86

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 links:

WWOX (HGNC:):

WWOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032241344).

BP6

Variant 16-78425018-C-G is Benign according to our data. Variant chr16-78425018-C-G is described in ClinVar as [Benign]. Clinvar id is 380943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78425018-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.082 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	7/9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 linkuse as main transcript	c.415C>G	p.Pro139Ala	missense_variant	6/8		NP_001278926.1	Q9NZC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.754C>G	p.Pro252Ala	missense_variant	7/9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1553

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0887

Gnomad SAS

AF:

0.0734

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0235

AC:

5866

AN:

249540

Hom.:

222

AF XY:

0.0237

AC XY:

3215

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.0562

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.0827

Gnomad SAS exome

AF:

0.0708

Gnomad FIN exome

AF:

0.00306

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.00880

AC:

12859

AN:

1461774

Hom.:

505

Cov.:

AF XY:

0.0103

AC XY:

7491

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0553

Gnomad4 ASJ exome

AF:

0.00409

Gnomad4 EAS exome

AF:

0.0782

Gnomad4 SAS exome

AF:

0.0678

Gnomad4 FIN exome

AF:

0.00281

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0102

AC:

1558

AN:

152242

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

904

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.0392

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0887

Gnomad4 SAS

AF:

0.0730

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00437

Hom.:

Bravo

AF:

0.0110

ESP6500AA

AF:

0.000994

AC:

ESP6500EA

AF:

0.000478

AC:

ExAC

AF:

0.0231

AC:

2797

Asia WGS

AF:

0.0740

AC:

257

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2017	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive spinocerebellar ataxia 12

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.46

N;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.1

D;D;.

REVEL

Uncertain

0.56

Sift

Benign

0.33

T;T;.

Sift4G

Uncertain

0.056

T;T;T

Polyphen

0.79

P;.;.

Vest4

0.66

ClinPred

0.028

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over