16-78099780-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_016373.4(WWOX):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000451 in 1,550,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

WWOX
NM_016373.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.49

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 Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 114 codons. Genomic position: 78115085. Lost 0.273 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-78099780-T-C is Pathogenic according to our data. Variant chr16-78099780-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1898392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 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.2T>C	p.Met1?	start_lost	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000191

AC:

AN:

156814

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

84466

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000279

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1398430

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000845

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000277

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000172

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the WWOX mRNA. The next in-frame methionine is located at codon 114. This variant is present in population databases (rs758588684, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1898392). This variant disrupts a region of the WWOX protein in which other variant(s) (p.Pro47Thr) have been determined to be pathogenic (PMID: 24369382). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;.;.;T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.51

PROVEAN

Benign

-1.5

N;.;N;N;N;D;N;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

D;.;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

0.97

D;.;D;D;.;P;D;.

Vest4

0.83

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);Gain of glycosylation at M1 (P = 0.0558);

MVP

0.97

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.28

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