NM_016373.4:c.1056+297448T>C

Variant names:

• chr16-78730200-T-C
• rs8047442
• NM_016373.4:c.1056+297448T>C

Variant summary

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

The NM_016373.4(WWOX):​c.1056+297448T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 151,952 control chromosomes in the GnomAD database, including 8,797 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 0.34 (8797 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.588
• Publications: 7 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

ENSG00000304647 (HGNC:):

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 (SAS) allele frequency at 95% confidence interval = 0.442 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.1056+297448T>C		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.717+297448T>C		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.1056+297448T>C		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.*15+38908T>C		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.410-481408T>C		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50879 AN: 151834 Hom.: 8777 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.335 AC: 50946 AN: 151952 Hom.: 8797 Cov.: 32 AF XY: 0.335 AC XY: 24852 AN XY: 74294

African (AFR) AF: 0.399 AC: 16535 AN: 41418

American (AMR) AF: 0.281 AC: 4293 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1200 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2166 AN: 5130

South Asian (SAS) AF: 0.458 AC: 2204 AN: 4808

European-Finnish (FIN) AF: 0.278 AC: 2938 AN: 10586

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.303 AC: 20592 AN: 67950

Other (OTH) AF: 0.328 AC: 692 AN: 2112

Alfa AF: 0.296 Hom.: 3805

Bravo AF: 0.335

Asia WGS AF: 0.455 AC: 1582 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.37
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8047442; hg19: chr16-78764097;