chr16-78835648-C-T

Variant names:

• chr16-78835648-C-T
• rs4888855
• NM_016373.4:c.1057-375960C>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.1057-375960C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,094 control chromosomes in the GnomAD database, including 4,607 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 0.24 (4607 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 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.1057-375960C>T		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-375960C>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.1057-375960C>T		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-375960C>T		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-375960C>T		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36936 AN: 151974 Hom.: 4605 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.243 AC: 36954 AN: 152094 Hom.: 4607 Cov.: 33 AF XY: 0.247 AC XY: 18342 AN XY: 74344

African (AFR) AF: 0.176 AC: 7289 AN: 41498

American (AMR) AF: 0.268 AC: 4099 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1141 AN: 5178

South Asian (SAS) AF: 0.317 AC: 1527 AN: 4820

European-Finnish (FIN) AF: 0.248 AC: 2613 AN: 10552

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18074 AN: 67972

Other (OTH) AF: 0.288 AC: 608 AN: 2108

Alfa AF: 0.256 Hom.: 6526

Bravo AF: 0.240

Asia WGS AF: 0.261 AC: 912 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	0.051
DANN	Benign	0.59
PhyloP100		-1.4
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: rs4888855; hg19: chr16-78869545;