16-78828488-C-T

Variant names:

• chr16-78828488-C-T
• rs11150104
• NM_016373.4:c.1057-383120C>T

Variant summary

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

The NM_016373.4(WWOX):​c.1057-383120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 151,868 control chromosomes in the GnomAD database, including 6,282 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 0.27 (6282 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• Publications: 4 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 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.1057-383120C>T		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-383120C>T		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.1057-383120C>T		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-383120C>T		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-383120C>T		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40279 AN: 151760 Hom.: 6281 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.288

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

GnomAD4 genome AF: 0.265 AC: 40282 AN: 151868 Hom.: 6282 Cov.: 32 AF XY: 0.270 AC XY: 20053 AN XY: 74170

African (AFR) AF: 0.103 AC: 4250 AN: 41450

American (AMR) AF: 0.308 AC: 4697 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3472

East Asian (EAS) AF: 0.384 AC: 1981 AN: 5154

South Asian (SAS) AF: 0.289 AC: 1384 AN: 4796

European-Finnish (FIN) AF: 0.376 AC: 3945 AN: 10500

Middle Eastern (MID) AF: 0.421 AC: 122 AN: 290

European-Non Finnish (NFE) AF: 0.317 AC: 21524 AN: 67956

Other (OTH) AF: 0.284 AC: 597 AN: 2104

Alfa AF: 0.211 Hom.: 727

Bravo AF: 0.257

Asia WGS AF: 0.304 AC: 1058 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.32
PhyloP100		0.35
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: rs11150104; hg19: chr16-78862385;