chr16-78107367-A-C

Variant names:

• chr16-78107367-A-C
• rs8045450
• NM_016373.4:c.108-1056A>C

Variant summary

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

The NM_016373.4(WWOX):​c.108-1056A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 152,180 control chromosomes in the GnomAD database, including 12,409 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 0.39 (12409 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 6 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 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.108-1056A>C		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.-167-2411A>C		intron	N/A	NP_001278926.1
	WWOX	NM_130791.5		c.108-1056A>C		intron	N/A	NP_570607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.108-1056A>C		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000408984.7	TSL:1	c.108-1056A>C		intron	N/A	ENSP00000386161.3
	WWOX	ENST00000402655.6	TSL:1	c.108-1056A>C		intron	N/A	ENSP00000384238.2

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59869 AN: 152062 Hom.: 12378 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.394 AC: 59947 AN: 152180 Hom.: 12409 Cov.: 32 AF XY: 0.390 AC XY: 28994 AN XY: 74392

African (AFR) AF: 0.535 AC: 22217 AN: 41514

American (AMR) AF: 0.316 AC: 4838 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1341 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1160 AN: 5176

South Asian (SAS) AF: 0.264 AC: 1276 AN: 4830

European-Finnish (FIN) AF: 0.366 AC: 3875 AN: 10588

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24110 AN: 67986

Other (OTH) AF: 0.356 AC: 752 AN: 2114

Alfa AF: 0.360 Hom.: 5275

Bravo AF: 0.399

Asia WGS AF: 0.229 AC: 799 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.43
DANN	Benign	0.48
PhyloP100		-1.3
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: rs8045450; hg19: chr16-78141264;