rs11545028

Positions:

• chr16-78099774-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.-5C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,541,828 control chromosomes in the GnomAD database, including 80,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6339 hom., cov: 33)
  • Exomes 𝑓: 0.32 (74319 hom.)
• Consequence: WWOX NM_016373.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.258

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 16-78099774-C-T is Benign according to our data. Variant chr16-78099774-C-T is described in ClinVar as [Benign]. Clinvar id is 260735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.-5C>T		5_prime_UTR_variant	1/9	ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.-5C>T		5_prime_UTR_variant	1/9	1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42307 AN: 152068 Hom.: 6335 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.272

GnomAD3 exomes AF: 0.300 AC: 44471 AN: 148386 Hom.: 6949 AF XY: 0.301 AC XY: 24052 AN XY: 79884

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.255

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.324 AC: 449999 AN: 1389642 Hom.: 74319 Cov.: 34 AF XY: 0.322 AC XY: 220932 AN XY: 685744

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.278 AC: 42315 AN: 152186 Hom.: 6339 Cov.: 33 AF XY: 0.277 AC XY: 20642 AN XY: 74400

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.269

Alfa AF: 0.322 Hom.: 11546

Bravo AF: 0.268

Asia WGS AF: 0.191 AC: 665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 46% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 43. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Developmental and epileptic encephalopathy, 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Autosomal recessive spinocerebellar ataxia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs11545028; hg19: chr16-78133671; COSMIC: COSV63434361; COSMIC: COSV63434361;