rs11545029

Positions:

Variant summary

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

The NM_016373.4(WWOX):c.535G>A(p.Ala179Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.533 in 1,613,106 control chromosomes in the GnomAD database, including 246,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 17197 hom., cov: 32)

Exomes 𝑓: 0.54 ( 229044 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.64

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:

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=0.0012559593).

BP6

Variant 16-78386878-G-A is Benign according to our data. Variant chr16-78386878-G-A is described in ClinVar as [Benign]. Clinvar id is 260740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78386878-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.535G>A	p.Ala179Thr	missense_variant	6/9	ENST00000566780.6
WWOX	NM_001291997.2 linkuse as main transcript	c.196G>A	p.Ala66Thr	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.535G>A	p.Ala179Thr	missense_variant	6/9	1	NM_016373.4	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66433

AN:

151856

Hom.:

17201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.650

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.0737

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.598

Gnomad OTH

AF:

0.456

GnomAD3 exomes

AF:

0.451

AC:

112445

AN:

249274

Hom.:

29632

AF XY:

0.457

AC XY:

61764

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.491

Gnomad EAS exome

AF:

0.0622

Gnomad SAS exome

AF:

0.268

Gnomad FIN exome

AF:

0.584

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.543

AC:

793001

AN:

1461132

Hom.:

229044

Cov.:

AF XY:

0.537

AC XY:

390311

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.368

Gnomad4 ASJ exome

AF:

0.486

Gnomad4 EAS exome

AF:

0.0659

Gnomad4 SAS exome

AF:

0.275

Gnomad4 FIN exome

AF:

0.585

Gnomad4 NFE exome

AF:

0.601

Gnomad4 OTH exome

AF:

0.497

GnomAD4 genome

AF:

0.437

AC:

66430

AN:

151974

Hom.:

17197

Cov.:

AF XY:

0.432

AC XY:

32071

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.197

Gnomad4 AMR

AF:

0.424

Gnomad4 ASJ

AF:

0.503

Gnomad4 EAS

AF:

0.0740

Gnomad4 SAS

AF:

0.257

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.598

Gnomad4 OTH

AF:

0.455

Alfa

AF:

0.550

Hom.:

43168

Bravo

AF:

0.417

TwinsUK

AF:

0.596

AC:

2211

ALSPAC

AF:

0.602

AC:

2321

ESP6500AA

AF:

0.195

AC:

757

ESP6500EA

AF:

0.583

AC:

4823

ExAC

AF:

0.450

AC:

54428

Asia WGS

AF:

0.170

AC:

592

AN:

3478

EpiCase

AF:

0.594

EpiControl

AF:

0.595

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 69% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 64. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 2021

- -

Developmental and epileptic encephalopathy, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2017

- -

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

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.56

N;N

MutationTaster

Benign

0.00092

P;P;P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.99

N;N

Sift

Benign

0.53

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.098

B;.

Vest4

0.49

ClinPred

0.011

GERP RS

5.5

Varity_R

0.40

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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