rs383362

Positions:

• chr16-79211923-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000566780.6(WWOX):​c.*127G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,541,148 control chromosomes in the GnomAD database, including 221,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17163 hom., cov: 33)
  • Exomes 𝑓: 0.53 (204174 hom.)
• Consequence: WWOX ENST00000566780.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.90

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]

MAF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7422438E-4).
• BP6: Variant 16-79211923-G-T is Benign according to our data. Variant chr16-79211923-G-T is described in ClinVar as [Benign]. Clinvar id is 1247128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWOX	NM_016373.4	c.*127G>T		3_prime_UTR_variant	9/9	ENST00000566780.6	NP_057457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.*127G>T		3_prime_UTR_variant	9/9	1	NM_016373.4	ENSP00000457230	P1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69715 AN: 151992 Hom.: 17157 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.480

GnomAD3 exomes AF: 0.436 AC: 64037 AN: 146858 Hom.: 15752 AF XY: 0.442 AC XY: 35058 AN XY: 79310

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.532 AC: 739425 AN: 1389038 Hom.: 204174 Cov.: 82 AF XY: 0.529 AC XY: 362518 AN XY: 685916

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.534

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.574

Gnomad4 OTH exome AF: 0.495

GnomAD4 genome AF: 0.459 AC: 69747 AN: 152110 Hom.: 17163 Cov.: 33 AF XY: 0.450 AC XY: 33467 AN XY: 74368

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.536

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.545

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.474

Alfa AF: 0.530 Hom.: 49056

Bravo AF: 0.442

TwinsUK AF: 0.567 AC: 2103

ALSPAC AF: 0.574 AC: 2214

ExAC AF: 0.366 AC: 33799

Asia WGS AF: 0.242 AC: 842 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 54% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 50. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.5
DANN	Benign	0.78
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.00017	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.092
Sift	Benign	0.44	T
Sift4G	Benign	0.67	T
Polyphen		0.92	P
Vest4		0.20
ClinPred		0.020	T
GERP RS		1.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs383362; hg19: chr16-79245820; COSMIC: COSV68342466; COSMIC: COSV68342466;