rs3764340

Positions:

chr16-78432540-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.844C>G(p.Pro282Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,098 control chromosomes in the GnomAD database, including 3,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 476 hom., cov: 32)

Exomes 𝑓: 0.060 ( 2915 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.57

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=0.0044485033).

BP6

Variant 16-78432540-C-G is Benign according to our data. Variant chr16-78432540-C-G is described in ClinVar as [Benign]. Clinvar id is 260745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.844C>G	p.Pro282Ala	missense_variant	8/9	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2 linkuse as main transcript	c.505C>G	p.Pro169Ala	missense_variant	7/8		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.844C>G	p.Pro282Ala	missense_variant	8/9	1	NM_016373.4	ENSP00000457230	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.0735

AC:

11184

AN:

152100

Hom.:

477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0959

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0796

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.0916

Gnomad SAS

AF:

0.0919

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0575

Gnomad OTH

AF:

0.0686

GnomAD3 exomes

AF:

0.0711

AC:

17732

AN:

249482

Hom.:

688

AF XY:

0.0707

AC XY:

9568

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.0943

Gnomad AMR exome

AF:

0.0797

Gnomad ASJ exome

AF:

0.0980

Gnomad EAS exome

AF:

0.0867

Gnomad SAS exome

AF:

0.0893

Gnomad FIN exome

AF:

0.0560

Gnomad NFE exome

AF:

0.0583

Gnomad OTH exome

AF:

0.0710

GnomAD4 exome

AF:

0.0595

AC:

87031

AN:

1461880

Hom.:

2915

Cov.:

AF XY:

0.0601

AC XY:

43702

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.100

Gnomad4 AMR exome

AF:

0.0797

Gnomad4 ASJ exome

AF:

0.0987

Gnomad4 EAS exome

AF:

0.0814

Gnomad4 SAS exome

AF:

0.0875

Gnomad4 FIN exome

AF:

0.0610

Gnomad4 NFE exome

AF:

0.0532

Gnomad4 OTH exome

AF:

0.0645

GnomAD4 genome

AF:

0.0736

AC:

11203

AN:

152218

Hom.:

476

Cov.:

AF XY:

0.0739

AC XY:

5500

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0960

Gnomad4 AMR

AF:

0.0800

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.0916

Gnomad4 SAS

AF:

0.0918

Gnomad4 FIN

AF:

0.0540

Gnomad4 NFE

AF:

0.0575

Gnomad4 OTH

AF:

0.0683

Alfa

AF:

0.0611

Hom.:

241

Bravo

AF:

0.0721

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0503

AC:

194

ESP6500AA

AF:

0.0865

AC:

340

ESP6500EA

AF:

0.0592

AC:

491

ExAC

AF:

0.0743

AC:

8977

Asia WGS

AF:

0.0890

AC:

312

AN:

3478

EpiCase

AF:

0.0547

EpiControl

AF:

0.0549

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 05, 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

Labcorp Genetics (formerly Invitae), Labcorp

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

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

0.30

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;T;T

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.2

L;L;.

MutationTaster

Benign

1.2e-9

P;P;P;P;P

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.0

D;D;.

REVEL

Uncertain

0.43

Sift

Benign

0.066

T;T;.

Sift4G

Benign

0.54

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.42

ClinPred

0.045

GERP RS

5.9

Varity_R

0.22

gMVP

0.78

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