rs17635945

Variant names:

• chr16-78956889-A-G
• rs17635945
• NM_016373.4:c.1057-254719A>G

Variant summary

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

The NM_016373.4(WWOX):​c.1057-254719A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 152,256 control chromosomes in the GnomAD database, including 461 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 0.067 (461 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.685
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.099 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-254719A>G		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-254719A>G		intron_variant	Intron 7 of 7		NP_001278926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.1057-254719A>G		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10188 AN: 152138 Hom.: 462 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.0650

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0888

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

GnomAD4 genome AF: 0.0669 AC: 10181 AN: 152256 Hom.: 461 Cov.: 32 AF XY: 0.0633 AC XY: 4714 AN XY: 74438

African (AFR) AF: 0.0193 AC: 804 AN: 41564

American (AMR) AF: 0.0647 AC: 990 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0616 AC: 297 AN: 4818

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10610

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6867 AN: 68012

Other (OTH) AF: 0.0874 AC: 185 AN: 2116

Alfa AF: 0.0781 Hom.: 67

Bravo AF: 0.0661

Asia WGS AF: 0.0280 AC: 99 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.46
PhyloP100		-0.69
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: rs17635945; hg19: chr16-78990786;