16-78432581-G-A

Position:

chr16-78432581-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_016373.4(WWOX):c.885G>A(p.Arg295=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00891 in 1,614,140 control chromosomes in the GnomAD database, including 114 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 0.0090 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 101 hom. )

Consequence

WWOX
NM_016373.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.0280

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 16-78432581-G-A is Benign according to our data. Variant chr16-78432581-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212617.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.

BP7

Synonymous conserved (PhyloP=-0.028 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00899 (1368/152252) while in subpopulation NFE AF= 0.00806 (548/68030). AF 95% confidence interval is 0.0075. There are 13 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.885G>A	p.Arg295=	synonymous_variant	8/9	ENST00000566780.6
WWOX	NM_001291997.2 linkuse as main transcript	c.546G>A	p.Arg182=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.885G>A	p.Arg295=	synonymous_variant	8/9	1	NM_016373.4	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00900

AC:

1369

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00606

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0416

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00805

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00857

AC:

2139

AN:

249566

Hom.:

AF XY:

0.00840

AC XY:

1137

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00646

Gnomad AMR exome

AF:

0.00446

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0398

Gnomad NFE exome

AF:

0.00779

Gnomad OTH exome

AF:

0.00957

GnomAD4 exome

AF:

0.00890

AC:

13013

AN:

1461888

Hom.:

101

Cov.:

AF XY:

0.00862

AC XY:

6269

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00741

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.0370

Gnomad4 NFE exome

AF:

0.00890

Gnomad4 OTH exome

AF:

0.00758

GnomAD4 genome

AF:

0.00899

AC:

1368

AN:

152252

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

757

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00604

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0416

Gnomad4 NFE

AF:

0.00806

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00812

Hom.:

Bravo

AF:

0.00641

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00796

EpiControl

AF:

0.00812

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	WWOX: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2018	- -

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

Jan 30, 2024

- -

WWOX-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.2

DANN

Benign

0.68

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