chr16-78970900-T-C

Variant names:

• chr16-78970900-T-C
• rs11860206
• NM_016373.4:c.1057-240708T>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.1057-240708T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 151,758 control chromosomes in the GnomAD database, including 25,702 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 0.58 (25702 hom., cov: 29)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-240708T>C		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-240708T>C		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.1057-240708T>C		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87701 AN: 151638 Hom.: 25699 Cov.: 29

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.593

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.594

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

GnomAD4 genome AF: 0.578 AC: 87735 AN: 151758 Hom.: 25702 Cov.: 29 AF XY: 0.579 AC XY: 42922 AN XY: 74164

African (AFR) AF: 0.491 AC: 20308 AN: 41350

American (AMR) AF: 0.598 AC: 9104 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1896 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2472 AN: 5134

South Asian (SAS) AF: 0.605 AC: 2902 AN: 4798

European-Finnish (FIN) AF: 0.612 AC: 6460 AN: 10554

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.627 AC: 42590 AN: 67918

Other (OTH) AF: 0.589 AC: 1237 AN: 2100

Alfa AF: 0.507 Hom.: 2036

Bravo AF: 0.570

Asia WGS AF: 0.526 AC: 1831 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		0.98
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: rs11860206; hg19: chr16-79004797;