rs8050128

Variant names:

• chr16-78278600-C-A
• rs8050128
• NM_016373.4:c.517-108260C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.517-108260C>A variant causes a 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. 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_016373.4 intron
• Scores: Splicing: ADA: 0.00002942
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.736
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 586944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.517-108260C>A		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.178-108260C>A		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.517-3C>A		splice_region intron	N/A	NP_570607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.517-108260C>A		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.517-108260C>A		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.409+163446C>A		intron	N/A	ENSP00000384238.2

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

GnomAD2 exomes AF: 0.449 AC: 109000 AN: 242750 AF XY: 0.446

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 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

African (AFR) AF: 0.520 AC: 17239 AN: 33174

American (AMR) AF: 0.430 AC: 18973 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 13777 AN: 25658

East Asian (EAS) AF: 0.471 AC: 18514 AN: 39308

South Asian (SAS) AF: 0.406 AC: 34302 AN: 84422

European-Finnish (FIN) AF: 0.417 AC: 21999 AN: 52724

Middle Eastern (MID) AF: 0.532 AC: 3028 AN: 5688

European-Non Finnish (NFE) AF: 0.451 AC: 489215 AN: 1085106

Other (OTH) AF: 0.461 AC: 27306 AN: 59186

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

African (AFR) AF: 0.518 AC: 21430 AN: 41390

American (AMR) AF: 0.456 AC: 6960 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1869 AN: 3472

East Asian (EAS) AF: 0.476 AC: 2455 AN: 5162

South Asian (SAS) AF: 0.403 AC: 1943 AN: 4824

European-Finnish (FIN) AF: 0.418 AC: 4407 AN: 10548

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30370 AN: 67938

Other (OTH) AF: 0.476 AC: 1008 AN: 2116

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 16, 2021

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 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

Mar 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.6
DANN	Benign	0.45
PhyloP100		0.74
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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