rs3751832

Variant names:

• chr16-79180375-A-G
• rs3751832
• NM_016373.4:c.1057-31233A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_016373.4(WWOX):​c.1057-31233A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,244 control chromosomes in the GnomAD database, including 1,325 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 0.11 (1325 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.641
• Publications: 8 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-31233A>G		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-31233A>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.1057-31233A>G		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17220 AN: 152126 Hom.: 1326 Cov.: 33

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.114

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

GnomAD4 genome AF: 0.113 AC: 17215 AN: 152244 Hom.: 1325 Cov.: 33 AF XY: 0.119 AC XY: 8823 AN XY: 74426

African (AFR) AF: 0.0543 AC: 2257 AN: 41570

American (AMR) AF: 0.157 AC: 2397 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 303 AN: 3470

East Asian (EAS) AF: 0.345 AC: 1784 AN: 5166

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4816

European-Finnish (FIN) AF: 0.142 AC: 1507 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7310 AN: 68016

Other (OTH) AF: 0.116 AC: 246 AN: 2116

Alfa AF: 0.109 Hom.: 2220

Bravo AF: 0.112

Asia WGS AF: 0.255 AC: 889 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.57
PhyloP100		0.64
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: rs3751832; hg19: chr16-79214272;