rs144601717

Variant summary

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

The NM_016373.4(WWOX):c.293C>T(p.Pro98Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0141 in 1,614,118 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P98P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.014 ( 169 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.09

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=0.0043513775).

BP6

Variant 16-78115038-C-T is Benign according to our data. Variant chr16-78115038-C-T is described in ClinVar as [Benign]. Clinvar id is 241101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78115038-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0143 (2179/152236) while in subpopulation AMR AF= 0.0171 (261/15284). AF 95% confidence interval is 0.0154. There are 23 homozygotes in gnomad4. There are 1001 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
WWOX	NM_016373.4 linkuse as main transcript	c.293C>T	p.Pro98Leu	missense_variant	4/9	ENST00000566780.6
WWOX	NM_130791.5 linkuse as main transcript	c.293C>T	p.Pro98Leu	missense_variant	4/6
WWOX	NM_001291997.2 linkuse as main transcript	c.-47C>T		5_prime_UTR_variant	3/8
WWOX	NR_120436.3 linkuse as main transcript	n.532C>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.293C>T	p.Pro98Leu	missense_variant	4/9	1	NM_016373.4	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2177

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00376

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.0123

AC:

3075

AN:

249570

Hom.:

AF XY:

0.0119

AC XY:

1613

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0341

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00569

Gnomad FIN exome

AF:

0.00431

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0141

AC:

20542

AN:

1461882

Hom.:

169

Cov.:

AF XY:

0.0138

AC XY:

10020

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0147

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.0349

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00555

Gnomad4 FIN exome

AF:

0.00461

Gnomad4 NFE exome

AF:

0.0151

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0143

AC:

2179

AN:

152236

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

1001

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0164

Gnomad4 AMR

AF:

0.0171

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00376

Gnomad4 NFE

AF:

0.0149

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0160

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.0173

AC:

ESP6500EA

AF:

0.0144

AC:

118

ExAC

AF:

0.0112

AC:

1359

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 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	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Dec 27, 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

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;.;T;.;.

Eigen

Benign

0.077

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.74

T;T;T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;L;L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;D;D;D;D;D

Sift

Benign

0.044

D;D;D;D;D;D

Sift4G

Benign

0.091

T;D;D;D;D;T

Polyphen

0.60

P;B;P;.;B;.

Vest4

0.70

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.47

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