16-78099774-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_016373.4(WWOX):c.-5C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,541,828 control chromosomes in the GnomAD database, including 80,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6339 hom., cov: 33)

Exomes 𝑓: 0.32 ( 74319 hom. )

Consequence

WWOX
NM_016373.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.258

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive spinocerebellar ataxia 12
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
developmental and epileptic encephalopathy, 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WWOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 16-78099774-C-T is Benign according to our data. Variant chr16-78099774-C-T is described in ClinVar as [Benign]. Clinvar id is 260735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.-5C>T		5_prime_UTR_variant	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.-5C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42307

AN:

152068

Hom.:

6335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.272

GnomAD2 exomes

AF:

0.300

AC:

44471

AN:

148386

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.255

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.308

GnomAD4 exome

AF:

0.324

AC:

449999

AN:

1389642

Hom.:

74319

Cov.:

AF XY:

0.322

AC XY:

220932

AN XY:

685744

show subpopulations

African (AFR)

AF:

0.161

AC:

4926

AN:

30634

American (AMR)

AF:

0.254

AC:

8469

AN:

33354

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

8892

AN:

24558

East Asian (EAS)

AF:

0.209

AC:

7289

AN:

34938

South Asian (SAS)

AF:

0.255

AC:

19773

AN:

77680

European-Finnish (FIN)

AF:

0.352

AC:

17320

AN:

49218

Middle Eastern (MID)

AF:

0.260

AC:

1288

AN:

4948

European-Non Finnish (NFE)

AF:

0.338

AC:

364188

AN:

1076806

Other (OTH)

AF:

0.310

AC:

17854

AN:

57506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16135

32270

48404

64539

80674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

42315

AN:

152186

Hom.:

6339

Cov.:

AF XY:

0.277

AC XY:

20642

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.162

AC:

6745

AN:

41542

American (AMR)

AF:

0.263

AC:

4026

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1296

AN:

3468

East Asian (EAS)

AF:

0.220

AC:

1132

AN:

5148

South Asian (SAS)

AF:

0.246

AC:

1186

AN:

4828

European-Finnish (FIN)

AF:

0.364

AC:

3863

AN:

10600

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23128

AN:

67978

Other (OTH)

AF:

0.269

AC:

568

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1567

3135

4702

6270

7837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.318

Hom.:

17933

Bravo

AF:

0.268

Asia WGS

AF:

0.191

AC:

665

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 06, 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

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 43. Only high quality variants are reported. -

not provided

Benign:2

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 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

- -

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_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.26

PromoterAI

-0.18

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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16-78099774-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over