chr16-78198082-G-A

Variant names:

• chr16-78198082-G-A
• rs889420
• NM_016373.4:c.516+33793G>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.516+33793G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 152,098 control chromosomes in the GnomAD database, including 924 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 0.099 (924 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• 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: 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 (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.516+33793G>A		intron_variant	Intron 5 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.177+33793G>A		intron_variant	Intron 4 of 7		NP_001278926.1
WWOX	NM_130791.5	c.516+33793G>A		intron_variant	Intron 5 of 5		NP_570607.1
WWOX	NR_120436.3	n.755+33793G>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.516+33793G>A		intron_variant	Intron 5 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14992 AN: 151980 Hom.: 924 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.125

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

GnomAD4 genome AF: 0.0986 AC: 14990 AN: 152098 Hom.: 924 Cov.: 32 AF XY: 0.0971 AC XY: 7215 AN XY: 74336

African (AFR) AF: 0.0287 AC: 1190 AN: 41502

American (AMR) AF: 0.132 AC: 2016 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3468

East Asian (EAS) AF: 0.168 AC: 868 AN: 5172

South Asian (SAS) AF: 0.0761 AC: 366 AN: 4808

European-Finnish (FIN) AF: 0.0870 AC: 919 AN: 10562

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.127 AC: 8635 AN: 68000

Other (OTH) AF: 0.123 AC: 259 AN: 2110

Alfa AF: 0.0662 Hom.: 121

Bravo AF: 0.101

Asia WGS AF: 0.111 AC: 386 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	0.33
DANN	Benign	0.51
PhyloP100		-1.7
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: rs889420; hg19: chr16-78231979;