16-78109710-C-T

Variant names:

• chr16-78109710-C-T
• rs2287972
• NM_016373.4:c.173-68C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.173-68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,570,608 control chromosomes in the GnomAD database, including 186,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14551 hom., cov: 28)
  • Exomes 𝑓: 0.49 (171668 hom.)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-78109710-C-T is Benign according to our data. Variant chr16-78109710-C-T is described in ClinVar as Benign. ClinVar VariationId is 1295626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.173-68C>T		intron_variant	Intron 2 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.-167-68C>T		intron_variant	Intron 1 of 7		NP_001278926.1
WWOX	NM_130791.5	c.173-68C>T		intron_variant	Intron 2 of 5		NP_570607.1
WWOX	NR_120436.3	n.412-68C>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.173-68C>T		intron_variant	Intron 2 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63225 AN: 150972 Hom.: 14537 Cov.: 28

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.487 AC: 691229 AN: 1419520 Hom.: 171668 AF XY: 0.490 AC XY: 347020 AN XY: 708732

African (AFR) AF: 0.209 AC: 6819 AN: 32692

American (AMR) AF: 0.580 AC: 25794 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 12270 AN: 25862

East Asian (EAS) AF: 0.649 AC: 25597 AN: 39428

South Asian (SAS) AF: 0.554 AC: 47228 AN: 85298

European-Finnish (FIN) AF: 0.446 AC: 23728 AN: 53206

Middle Eastern (MID) AF: 0.508 AC: 2870 AN: 5652

European-Non Finnish (NFE) AF: 0.483 AC: 518687 AN: 1073864

Other (OTH) AF: 0.478 AC: 28236 AN: 59018

GnomAD4 genome AF: 0.419 AC: 63264 AN: 151088 Hom.: 14551 Cov.: 28 AF XY: 0.423 AC XY: 31215 AN XY: 73748

African (AFR) AF: 0.224 AC: 9227 AN: 41282

American (AMR) AF: 0.537 AC: 8137 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1609 AN: 3462

East Asian (EAS) AF: 0.630 AC: 3145 AN: 4992

South Asian (SAS) AF: 0.563 AC: 2664 AN: 4730

European-Finnish (FIN) AF: 0.441 AC: 4568 AN: 10358

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32332 AN: 67806

Other (OTH) AF: 0.475 AC: 998 AN: 2102

Alfa AF: 0.468 Hom.: 71975

Bravo AF: 0.416

Asia WGS AF: 0.618 AC: 2145 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 73. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.45
DANN	Benign	0.78
PhyloP100		-1.2
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: rs2287972; hg19: chr16-78143607; COSMIC: COSV63434259;