16-78958895-T-A

Variant names:

• chr16-78958895-T-A
• rs12596756
• NM_016373.4:c.1057-252713T>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.1057-252713T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 152,016 control chromosomes in the GnomAD database, including 22,046 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 0.53 (22046 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1057-252713T>A		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.718-252713T>A		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.1057-252713T>A		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80521 AN: 151900 Hom.: 22040 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.530 AC: 80567 AN: 152016 Hom.: 22046 Cov.: 32 AF XY: 0.536 AC XY: 39835 AN XY: 74304

African (AFR) AF: 0.453 AC: 18770 AN: 41448

American (AMR) AF: 0.611 AC: 9333 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2361 AN: 3470

East Asian (EAS) AF: 0.909 AC: 4706 AN: 5176

South Asian (SAS) AF: 0.650 AC: 3131 AN: 4814

European-Finnish (FIN) AF: 0.513 AC: 5417 AN: 10556

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.516 AC: 35046 AN: 67960

Other (OTH) AF: 0.560 AC: 1180 AN: 2108

Alfa AF: 0.510 Hom.: 2483

Bravo AF: 0.537

Asia WGS AF: 0.749 AC: 2601 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.78
PhyloP100		-0.11
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: rs12596756; hg19: chr16-78992792;