16-78970332-T-C

Variant names:

• chr16-78970332-T-C
• rs12716865
• NM_016373.4:c.1057-241276T>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.1057-241276T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,082 control chromosomes in the GnomAD database, including 31,886 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 0.64 (31886 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1057-241276T>C		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.718-241276T>C		intron	N/A	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-241276T>C		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000402655.6	TSL:1	c.410-241276T>C		intron	N/A	ENSP00000384238.2	Q9NZC7-6
	WWOX	ENST00000406884.6	TSL:1	c.517-241276T>C		intron	N/A	ENSP00000384495.2	Q9NZC7-5

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97985 AN: 151964 Hom.: 31866 Cov.: 33

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.638

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

GnomAD4 genome AF: 0.645 AC: 98055 AN: 152082 Hom.: 31886 Cov.: 33 AF XY: 0.641 AC XY: 47680 AN XY: 74328

African (AFR) AF: 0.718 AC: 29792 AN: 41506

American (AMR) AF: 0.621 AC: 9483 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2056 AN: 3466

East Asian (EAS) AF: 0.479 AC: 2470 AN: 5158

South Asian (SAS) AF: 0.606 AC: 2912 AN: 4806

European-Finnish (FIN) AF: 0.612 AC: 6464 AN: 10564

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42764 AN: 67998

Other (OTH) AF: 0.632 AC: 1335 AN: 2112

Alfa AF: 0.630 Hom.: 124534

Bravo AF: 0.646

Asia WGS AF: 0.544 AC: 1894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.72
PhyloP100		-0.0010
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: rs12716865; hg19: chr16-79004229;