chr16-79025103-T-C

Variant names:

• chr16-79025103-T-C
• rs1808447
• NM_016373.4:c.1057-186505T>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.1057-186505T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 152,192 control chromosomes in the GnomAD database, including 49,151 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 0.80 (49151 hom., cov: 33)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.550
• Publications: 2 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.934 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	NM_016373.4	MANE Select	c.1057-186505T>C		intron	N/A	NP_057457.1
	WWOX	NM_001291997.2		c.718-186505T>C		intron	N/A	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1057-186505T>C		intron	N/A	ENSP00000457230.1
	WWOX	ENST00000402655.6	TSL:1	c.410-186505T>C		intron	N/A	ENSP00000384238.2
	WWOX	ENST00000406884.6	TSL:1	c.517-186505T>C		intron	N/A	ENSP00000384495.2

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121971 AN: 152074 Hom.: 49102 Cov.: 33

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.802

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

GnomAD4 genome AF: 0.802 AC: 122074 AN: 152192 Hom.: 49151 Cov.: 33 AF XY: 0.804 AC XY: 59818 AN XY: 74398

African (AFR) AF: 0.842 AC: 34973 AN: 41528

American (AMR) AF: 0.846 AC: 12932 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2534 AN: 3472

East Asian (EAS) AF: 0.956 AC: 4929 AN: 5154

South Asian (SAS) AF: 0.797 AC: 3846 AN: 4826

European-Finnish (FIN) AF: 0.810 AC: 8571 AN: 10588

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51811 AN: 68008

Other (OTH) AF: 0.804 AC: 1702 AN: 2116

Alfa AF: 0.781 Hom.: 80146

Bravo AF: 0.808

Asia WGS AF: 0.876 AC: 3044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.5
DANN	Benign	0.65
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1808447; hg19: chr16-79059000;