rs74860463

Positions:

Variant summary

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

The NM_016373.4(WWOX):c.613C>A(p.His205Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,998 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. H205R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0063 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 14 hom. )

Consequence

WWOX
NM_016373.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

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=0.010043293).

BP6

Variant 16-78424877-C-A is Benign according to our data. Variant chr16-78424877-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 260743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78424877-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00633 (963/152242) while in subpopulation AFR AF= 0.0217 (902/41536). AF 95% confidence interval is 0.0205. There are 3 homozygotes in gnomad4. There are 431 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4 linkuse as main transcript	c.613C>A	p.His205Asn	missense_variant	7/9	ENST00000566780.6
WWOX	NM_001291997.2 linkuse as main transcript	c.274C>A	p.His92Asn	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6 linkuse as main transcript	c.613C>A	p.His205Asn	missense_variant	7/9	1	NM_016373.4	P1	Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

962

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00152

AC:

380

AN:

249514

Hom.:

AF XY:

0.00119

AC XY:

161

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.0221

Gnomad AMR exome

AF:

0.000927

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000564

AC:

825

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0208

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.00633

AC:

963

AN:

152242

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

431

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00696

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0196

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00176

AC:

213

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2017	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

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

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.31

T;.;T

Eigen

Benign

-0.0050

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.74

N;N;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

N;N;.

REVEL

Benign

0.14

Sift

Benign

0.70

T;T;.

Sift4G

Benign

0.59

T;T;T

Polyphen

0.20

B;.;.

Vest4

0.92

MVP

0.79

ClinPred

0.038

GERP RS

5.3

Varity_R

0.35

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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