16-79019046-A-G

Variant names:

• chr16-79019046-A-G
• rs7185820
• NM_016373.4:c.1057-192562A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016373.4(WWOX):​c.1057-192562A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 148,052 control chromosomes in the GnomAD database, including 3,553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3553 hom., cov: 28)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 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.1057-192562A>G		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-192562A>G		intron	N/A	NP_001278926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-192562A>G		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-192562A>G		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-192562A>G		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 32382 AN: 147950 Hom.: 3541 Cov.: 28

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.242

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.219 AC: 32426 AN: 148052 Hom.: 3553 Cov.: 28 AF XY: 0.223 AC XY: 16057 AN XY: 72066

African (AFR) AF: 0.186 AC: 7517 AN: 40458

American (AMR) AF: 0.263 AC: 3905 AN: 14832

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 885 AN: 3438

East Asian (EAS) AF: 0.340 AC: 1644 AN: 4834

South Asian (SAS) AF: 0.272 AC: 1215 AN: 4462

European-Finnish (FIN) AF: 0.253 AC: 2479 AN: 9794

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14019 AN: 66980

Other (OTH) AF: 0.247 AC: 508 AN: 2060

Alfa AF: 0.116 Hom.: 218

Bravo AF: 0.216

Asia WGS AF: 0.289 AC: 1001 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.12
PhyloP100		-2.8
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: rs7185820; hg19: chr16-79052943;