NM_016373.4:c.606-17G>A

Variant names:

• chr16-78424853-G-A
• rs4130513
• NM_016373.4:c.606-17G>A

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.606-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,034 control chromosomes in the GnomAD database, including 20,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (8191 hom., cov: 32)
  • Exomes 𝑓: 0.094 (12417 hom.)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.510
• Publications: 11 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=-0.87).
• BP6: Variant 16-78424853-G-A is Benign according to our data. Variant chr16-78424853-G-A is described in ClinVar as [Benign]. Clinvar id is 260742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.606-17G>A		intron_variant	Intron 6 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.267-17G>A		intron_variant	Intron 5 of 7		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.606-17G>A		intron_variant	Intron 6 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35326 AN: 151846 Hom.: 8161 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0906

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.133 AC: 33197 AN: 248764 AF XY: 0.126

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0939 AC: 137157 AN: 1461070 Hom.: 12417 Cov.: 32 AF XY: 0.0937 AC XY: 68082 AN XY: 726920

African (AFR) AF: 0.625 AC: 20800 AN: 33306

American (AMR) AF: 0.120 AC: 5366 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3483 AN: 26134

East Asian (EAS) AF: 0.169 AC: 6716 AN: 39688

South Asian (SAS) AF: 0.146 AC: 12566 AN: 86230

European-Finnish (FIN) AF: 0.0926 AC: 4947 AN: 53400

Middle Eastern (MID) AF: 0.137 AC: 792 AN: 5764

European-Non Finnish (NFE) AF: 0.0674 AC: 74968 AN: 1111480

Other (OTH) AF: 0.125 AC: 7519 AN: 60348

GnomAD4 genome AF: 0.233 AC: 35408 AN: 151964 Hom.: 8191 Cov.: 32 AF XY: 0.231 AC XY: 17144 AN XY: 74298

African (AFR) AF: 0.601 AC: 24859 AN: 41382

American (AMR) AF: 0.143 AC: 2189 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 449 AN: 3468

East Asian (EAS) AF: 0.187 AC: 967 AN: 5160

South Asian (SAS) AF: 0.150 AC: 722 AN: 4812

European-Finnish (FIN) AF: 0.0906 AC: 959 AN: 10586

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0706 AC: 4798 AN: 67980

Other (OTH) AF: 0.188 AC: 397 AN: 2108

Alfa AF: 0.119 Hom.: 3324

Bravo AF: 0.251

Asia WGS AF: 0.205 AC: 717 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

Jan 12, 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. -

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

Feb 04, 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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.87
CADD	Benign	0.88
DANN	Benign	0.45
PhyloP100		-0.51
PromoterAI		-0.0052	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4130513; hg19: chr16-78458750; COSMIC: COSV68343889; COSMIC: COSV68343889;