16-78109424-T-G

Variant names:

• chr16-78109424-T-G
• rs2287973
• NM_016373.4:c.173-354T>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.173-354T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,106 control chromosomes in the GnomAD database, including 9,183 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 0.33 (9183 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 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.173-354T>G		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.-167-354T>G		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.173-354T>G		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.173-354T>G		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.173-354T>G		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.173-354T>G		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50171 AN: 151988 Hom.: 9178 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.330 AC: 50198 AN: 152106 Hom.: 9183 Cov.: 32 AF XY: 0.335 AC XY: 24911 AN XY: 74342

African (AFR) AF: 0.175 AC: 7283 AN: 41518

American (AMR) AF: 0.432 AC: 6594 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1289 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1926 AN: 5174

South Asian (SAS) AF: 0.510 AC: 2454 AN: 4808

European-Finnish (FIN) AF: 0.372 AC: 3933 AN: 10566

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25378 AN: 67980

Other (OTH) AF: 0.387 AC: 818 AN: 2114

Alfa AF: 0.307 Hom.: 2957

Bravo AF: 0.325

Asia WGS AF: 0.486 AC: 1690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.020
DANN	Benign	0.30
PhyloP100		-1.9
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: rs2287973; hg19: chr16-78143321;