16-79211790-C-T

Variant names:

Variant summary

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

The ENST00000402655.6(WWOX):c.592C>T(p.Arg198Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,096 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 68 hom. )

Consequence

WWOX
ENST00000402655.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.71

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:

MAF (HGNC:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

MAF 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=0.0052375197).

BP6

Variant 16-79211790-C-T is Benign according to our data. Variant chr16-79211790-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-79211790-C-T is described in Lovd as [Likely_benign]. Variant chr16-79211790-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00631 (961/152342) while in subpopulation AMR AF= 0.00987 (151/15302). AF 95% confidence interval is 0.00859. There are 4 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.1239C>T	p.Ser413Ser	synonymous_variant	Exon 9 of 9	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.1239C>T	p.Ser413Ser	synonymous_variant	Exon 9 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

961

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00988

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00779

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00673

AC:

1673

AN:

248454

Hom.:

AF XY:

0.00678

AC XY:

915

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00699

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00500

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.00763

Gnomad OTH exome

AF:

0.00630

GnomAD4 exome

AF:

0.00769

AC:

11247

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

5529

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00678

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00483

Gnomad4 FIN exome

AF:

0.0168

Gnomad4 NFE exome

AF:

0.00816

Gnomad4 OTH exome

AF:

0.00749

GnomAD4 genome

AF:

0.00631

AC:

961

AN:

152342

Hom.:

Cov.:

AF XY:

0.00695

AC XY:

518

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00987

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.00779

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00555

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00614

AC:

742

EpiCase

AF:

0.00731

EpiControl

AF:

0.00711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 13, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 28

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WWOX: BP4, BS2 -

Autosomal recessive spinocerebellar ataxia 12

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

5.5

DANN

Uncertain

0.99

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.8

REVEL

Benign

0.041

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.055

Vest4

0.23

MVP

0.64

ClinPred

0.036

GERP RS

2.6

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