rs141361080

Positions:

chr16-78115103-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016373.4(WWOX):c.358C>T(p.Arg120Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00743 in 1,614,110 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 66 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.54

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=0.014221847).

BP6

Variant 16-78115103-C-T is Benign according to our data. Variant chr16-78115103-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 218734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78115103-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00572 (870/152222) while in subpopulation SAS AF= 0.0164 (79/4816). AF 95% confidence interval is 0.0135. There are 5 homozygotes in gnomad4. There are 464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
WWOX	NM_016373.4 linkuse as main transcript	c.358C>T	p.Arg120Trp	missense_variant	4/9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2 linkuse as main transcript	c.19C>T	p.Arg7Trp	missense_variant	3/8		NP_001278926.1
WWOX	NM_130791.5 linkuse as main transcript	c.358C>T	p.Arg120Trp	missense_variant	4/6		NP_570607.1
WWOX	NR_120436.3 linkuse as main transcript	n.597C>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.358C>T	p.Arg120Trp	missense_variant	4/9	1	NM_016373.4	ENSP00000457230	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

872

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0166

Gnomad FIN

AF:

0.00775

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00773

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00749

AC:

1869

AN:

249524

Hom.:

AF XY:

0.00803

AC XY:

1087

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00145

Gnomad SAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.00867

Gnomad NFE exome

AF:

0.00799

Gnomad OTH exome

AF:

0.00693

GnomAD4 exome

AF:

0.00761

AC:

11121

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00778

AC XY:

5656

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00313

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.00754

Gnomad4 OTH exome

AF:

0.00684

GnomAD4 genome

AF:

0.00572

AC:

870

AN:

152222

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

464

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00634

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.00775

Gnomad4 NFE

AF:

0.00772

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00690

Hom.:

Bravo

AF:

0.00461

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00162

AC:

ESP6500EA

AF:

0.00758

AC:

ExAC

AF:

0.00756

AC:

914

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00872

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	WWOX: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2018	This variant is associated with the following publications: (PMID: 30949922, 27884173, 21983861, 25612104, 11572989, 20480411, 24082139) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 11, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 26, 2015	- -

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

- -

WWOX-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2024

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). -

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

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

T;.;.;T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

MetaRNN

Benign

0.014

T;T;T;T;T;T

MetaSVM

Uncertain

0.058

MutationAssessor

Uncertain

2.2

M;M;M;.;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.017

D;D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;D;.

Vest4

0.71

MVP

0.87

ClinPred

0.025

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.70

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