rs12934985

chr16-78115170-A-Cchr16-78115170-A-Gchr16-78115170-A-T

Variant summary

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

The NM_016373.4(WWOX):c.409+16A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,652 control chromosomes in the GnomAD database, including 66,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4675 hom., cov: 33)
  • Exomes 𝑓: 0.29 (62023 hom.)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-78115170-A-C is Benign according to our data. Variant chr16-78115170-A-C is described in ClinVar as [Benign]. Clinvar id is 260738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.409+16A>C		intron_variant		ENST00000566780.6
WWOX	NM_001291997.2	c.70+16A>C		intron_variant
WWOX	NM_130791.5	c.409+16A>C		intron_variant
WWOX	NR_120436.3	n.648+16A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.409+16A>C		intron_variant		1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34230 AN: 152086 Hom.: 4672 Cov.: 33

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.262 AC: 65189 AN: 248674 Hom.: 9310 AF XY: 0.266 AC XY: 35862 AN XY: 135022

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.255

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.286 AC: 418320 AN: 1461448 Hom.: 62023 Cov.: 34 AF XY: 0.285 AC XY: 207177 AN XY: 727026

Gnomad4 AFR exome AF: 0.0471

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.330

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.225 AC: 34225 AN: 152204 Hom.: 4675 Cov.: 33 AF XY: 0.226 AC XY: 16808 AN XY: 74404

Gnomad4 AFR AF: 0.0566

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.209

Alfa AF: 0.163 Hom.: 386

Bravo AF: 0.210

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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	-0.83
Cadd	Benign	0.13
Dann	Benign	0.64

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: rs12934985; hg19: chr16-78149067; COSMIC: COSV63434372; COSMIC: COSV63434372;