rs140817689

Positions:

chr16-78164241-G-T

Variant summary

Our verdict is Benign. Variant got -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).

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

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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, M_CAP, MutationAssessor, PROVEAN, 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 id is 415952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.468G>T	p.Arg156Ser	missense_variant	5/9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 linkuse as main transcript	c.129G>T	p.Arg43Ser	missense_variant	4/8		NP_001278926.1	Q9NZC7
WWOX	NM_130791.5 linkuse as main transcript	c.468G>T	p.Arg156Ser	missense_variant	5/6		NP_570607.1	Q9NZC7-3
WWOX	NR_120436.3 linkuse as main transcript	n.707G>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.468G>T	p.Arg156Ser	missense_variant	5/9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

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

GnomAD3 exomes

AF:

0.00118

AC:

294

AN:

249432

Hom.:

AF XY:

0.00106

AC XY:

143

AN XY:

135312

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00650

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00281

Gnomad4 NFE exome

AF:

0.000311

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152318

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00888

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000642

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

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 26, 2024

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

WWOX-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

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). -

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

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.042

T;T;T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.6

H;H;H;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.96

MutPred

0.86

Loss of MoRF binding (P = 0.0148);Loss of MoRF binding (P = 0.0148);Loss of MoRF binding (P = 0.0148);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

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