Genetic Variant WWOX:c.173-68C>T (chr16-78109710-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_016373.4(WWOX):c.173-68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,570,608 control chromosomes in the GnomAD database, including 186,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14551 hom., cov: 28)

Exomes 𝑓: 0.49 ( 171668 hom. )

Consequence

WWOX
NM_016373.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.23

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-78109710-C-T is Benign according to our data. Variant chr16-78109710-C-T is described in ClinVar as [Benign]. Clinvar id is 1295626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4 link	c.173-68C>T	intron_variant	Intron 2 of 8	ENST00000566780.6	NP_057457.1	Q9NZC7-1A0A411HBC7
WWOX	NM_001291997.2 link	c.-167-68C>T	intron_variant	Intron 1 of 7		NP_001278926.1	Q9NZC7
WWOX	NM_130791.5 link	c.173-68C>T	intron_variant	Intron 2 of 5		NP_570607.1	Q9NZC7-3
WWOX	NR_120436.3 link	n.412-68C>T	intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6 link	c.173-68C>T		intron_variant	Intron 2 of 8	1	NM_016373.4	ENSP00000457230.1		Q9NZC7-1

Frequencies

GnomAD3 genomes

AF:

0.419

AC:

63225

AN:

150972

Hom.:

14537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.465

Gnomad EAS

AF:

0.629

Gnomad SAS

AF:

0.563

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.477

Gnomad OTH

AF:

0.470

GnomAD4 exome

AF:

0.487

AC:

691229

AN:

1419520

Hom.:

171668

AF XY:

0.490

AC XY:

347020

AN XY:

708732

show subpopulations

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.580

Gnomad4 ASJ exome

AF:

0.474

Gnomad4 EAS exome

AF:

0.649

Gnomad4 SAS exome

AF:

0.554

Gnomad4 FIN exome

AF:

0.446

Gnomad4 NFE exome

AF:

0.483

Gnomad4 OTH exome

AF:

0.478

GnomAD4 genome

AF:

0.419

AC:

63264

AN:

151088

Hom.:

14551

Cov.:

AF XY:

0.423

AC XY:

31215

AN XY:

73748

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.537

Gnomad4 ASJ

AF:

0.465

Gnomad4 EAS

AF:

0.630

Gnomad4 SAS

AF:

0.563

Gnomad4 FIN

AF:

0.441

Gnomad4 NFE

AF:

0.477

Gnomad4 OTH

AF:

0.475

Alfa

AF:

0.482

Hom.:

36518

Bravo

AF:

0.416

Asia WGS

AF:

0.618

AC:

2145

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

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 78% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 73. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.45

DANN

Benign

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