16-78918542-A-G

Variant names:

• chr16-78918542-A-G
• rs9923451
• NM_016373.4:c.1057-293066A>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.1057-293066A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 152,012 control chromosomes in the GnomAD database, including 65,064 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 0.92 (65064 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 14 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1057-293066A>G		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-293066A>G		intron	N/A	NP_001278926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-293066A>G		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-293066A>G		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-293066A>G		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.919 AC: 139637 AN: 151892 Hom.: 65033 Cov.: 32

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.963

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.986

Gnomad FIN AF: 0.981

Gnomad MID AF: 0.971

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.944

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

GnomAD4 genome AF: 0.919 AC: 139716 AN: 152012 Hom.: 65064 Cov.: 32 AF XY: 0.921 AC XY: 68396 AN XY: 74292

African (AFR) AF: 0.750 AC: 31039 AN: 41372

American (AMR) AF: 0.963 AC: 14723 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3428 AN: 3470

East Asian (EAS) AF: 0.938 AC: 4824 AN: 5142

South Asian (SAS) AF: 0.987 AC: 4759 AN: 4824

European-Finnish (FIN) AF: 0.981 AC: 10392 AN: 10598

Middle Eastern (MID) AF: 0.966 AC: 282 AN: 292

European-Non Finnish (NFE) AF: 0.991 AC: 67372 AN: 67996

Other (OTH) AF: 0.942 AC: 1990 AN: 2112

Alfa AF: 0.971 Hom.: 227214

Bravo AF: 0.908

Asia WGS AF: 0.961 AC: 3343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.016
DANN	Benign	0.21
PhyloP100		-2.4
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: rs9923451; hg19: chr16-78952439;