rs8050128

Positions:

• chr16-78278600-C-A
• chr16-78278600-C-G
• chr16-78278600-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130791.5(WWOX):​c.517-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,581,356 control chromosomes in the GnomAD database, including 166,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16822 hom., cov: 32)
  • Exomes 𝑓: 0.45 (149745 hom.)
• Consequence: WWOX NM_130791.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002942
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.736

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-78278600-C-A is Benign according to our data. Variant chr16-78278600-C-A is described in ClinVar as [Benign]. Clinvar id is 586944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78278600-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4	c.517-108260C>A		intron_variant		ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.178-108260C>A		intron_variant			NP_001278926.1
WWOX	NM_130791.5	c.517-3C>A		splice_region_variant, intron_variant			NP_570607.1
WWOX	NR_120436.3	n.756-3C>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.517-108260C>A		intron_variant		1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70874 AN: 151814 Hom.: 16799 Cov.: 32

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.449 AC: 109000 AN: 242750 Hom.: 24955 AF XY: 0.446 AC XY: 58704 AN XY: 131484

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.537

Gnomad EAS exome AF: 0.478

Gnomad SAS exome AF: 0.403

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.451 AC: 644353 AN: 1429424 Hom.: 149745 Cov.: 34 AF XY: 0.449 AC XY: 319603 AN XY: 711194

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.537

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.467 AC: 70939 AN: 151932 Hom.: 16822 Cov.: 32 AF XY: 0.464 AC XY: 34454 AN XY: 74258

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.403

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.476

Alfa AF: 0.462 Hom.: 8176

Bravo AF: 0.475

Asia WGS AF: 0.481 AC: 1666 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 33. Only high quality variants are reported. -

WWOX-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.6
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs8050128; hg19: chr16-78312497; COSMIC: COSV63437473;