rs66481974

Positions:

• chr16-79211594-T-C
• chr16-79211594-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016373.4(WWOX):​c.1057-14T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,614,050 control chromosomes in the GnomAD database, including 1,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (120 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1565 hom.)
• Consequence: WWOX NM_016373.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.909

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 (BayesDel_noAF=-0.8).
• BP6: Variant 16-79211594-T-C is Benign according to our data. Variant chr16-79211594-T-C is described in ClinVar as [Benign]. Clinvar id is 260736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0372 (5658/152262) while in subpopulation NFE AF= 0.0474 (3226/68028). AF 95% confidence interval is 0.0461. There are 120 homozygotes in gnomad4. There are 2802 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 120 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWOX	NM_016373.4	c.1057-14T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000566780.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWOX	ENST00000566780.6	c.1057-14T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016373.4	P1

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5656 AN: 152144 Hom.: 120 Cov.: 33

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0373 AC: 9248 AN: 248250 Hom.: 193 AF XY: 0.0382 AC XY: 5149 AN XY: 134938

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0333

Gnomad EAS exome AF: 0.0237

Gnomad SAS exome AF: 0.0339

Gnomad FIN exome AF: 0.0621

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0440 AC: 64297 AN: 1461788 Hom.: 1565 Cov.: 84 AF XY: 0.0442 AC XY: 32151 AN XY: 727206

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0327

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.0349

Gnomad4 FIN exome AF: 0.0612

Gnomad4 NFE exome AF: 0.0465

Gnomad4 OTH exome AF: 0.0421

GnomAD4 genome AF: 0.0372 AC: 5658 AN: 152262 Hom.: 120 Cov.: 33 AF XY: 0.0376 AC XY: 2802 AN XY: 74434

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.0263

Gnomad4 SAS AF: 0.0351

Gnomad4 FIN AF: 0.0641

Gnomad4 NFE AF: 0.0474

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0277 Hom.: 17

Bravo AF: 0.0328

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.80
CADD	Benign	8.1
DANN	Benign	0.73

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: rs66481974; hg19: chr16-79245491;