rs199511589

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_016373.4(WWOX):c.562C>A(p.Arg188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.00028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.65

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1975807).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000477 (698/1461830) while in subpopulation NFE AF= 0.000589 (655/1111970). AF 95% confidence interval is 0.000551. There are 0 homozygotes in gnomad4_exome. There are 329 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.562C>A	p.Arg188Ser	missense_variant	6/9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 linkuse as main transcript	c.223C>A	p.Arg75Ser	missense_variant	5/8		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.562C>A	p.Arg188Ser	missense_variant	6/9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000265

AC:

AN:

249382

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000477

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000477

AC:

698

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000452

AC XY:

329

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000589

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000276

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000604

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	WWOX: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25411445) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -

Malignant tumor of esophagus;C3280452:Autosomal recessive spinocerebellar ataxia 12;C4015519:Developmental and epileptic encephalopathy, 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 188 of the WWOX protein (p.Arg188Ser). This variant is present in population databases (rs199511589, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of WWOX-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 410086). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WWOX protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.096

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.0073

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.99

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.076

Sift

Benign

0.26

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.049

B;.

Vest4

0.42

MVP

0.76

ClinPred

0.56

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.49

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