rs8047300

Variant names:

• chr16-79023052-C-A
• rs8047300
• NM_016373.4:c.1057-188556C>A

Variant summary

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

The NM_016373.4(WWOX):​c.1057-188556C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 149,200 control chromosomes in the GnomAD database, including 40,242 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 0.74 (40242 hom., cov: 30)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 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.1057-188556C>A		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.718-188556C>A		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.1057-188556C>A		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000402655.6	TSL:1	c.410-188556C>A		intron	N/A	ENSP00000384238.2	Q9NZC7-6
	WWOX	ENST00000406884.6	TSL:1	c.517-188556C>A		intron	N/A	ENSP00000384495.2	Q9NZC7-5

Frequencies

GnomAD3 genomes AF: 0.739 AC: 110116 AN: 149100 Hom.: 40214 Cov.: 30

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.741

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

GnomAD4 genome AF: 0.739 AC: 110191 AN: 149200 Hom.: 40242 Cov.: 30 AF XY: 0.733 AC XY: 53496 AN XY: 72934

African (AFR) AF: 0.780 AC: 30862 AN: 39584

American (AMR) AF: 0.756 AC: 11386 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2358 AN: 3454

East Asian (EAS) AF: 0.854 AC: 4380 AN: 5130

South Asian (SAS) AF: 0.675 AC: 3223 AN: 4774

European-Finnish (FIN) AF: 0.659 AC: 6815 AN: 10348

Middle Eastern (MID) AF: 0.667 AC: 192 AN: 288

European-Non Finnish (NFE) AF: 0.723 AC: 48841 AN: 67558

Other (OTH) AF: 0.745 AC: 1552 AN: 2084

Alfa AF: 0.717 Hom.: 42417

Bravo AF: 0.742

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.086
DANN	Benign	0.31
PhyloP100		-1.1
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: rs8047300; hg19: chr16-79056949;