rs140060332

chr16-79211799-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The ENST00000402655.6(WWOX):c.601G>T(p.Gly201Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,018 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (64 hom.)
• Consequence: WWOX ENST00000402655.6 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.70

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 -14 ACMG points.

• PM4: Stoplost variant in ENST00000402655.6 Downstream stopcodon found after 352 codons.
• BP6: Variant 16-79211799-G-T is Benign according to our data. Variant chr16-79211799-G-T is described in ClinVar as [Benign]. Clinvar id is 382759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.003 (457/152332) while in subpopulation AMR AF= 0.0233 (356/15306). AF 95% confidence interval is 0.0213. There are 4 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00762 AC: 1893 AN: 248328 Hom.: 37 AF XY: 0.00570 AC XY: 769 AN XY: 135010

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.0468

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00202 AC: 2948 AN: 1461686 Hom.: 64 Cov.: 89 AF XY: 0.00172 AC XY: 1252 AN XY: 727160

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74490

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000689 Hom.: 0

Bravo AF: 0.00496

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00553 AC: 669

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 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. -

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

clinical testing

Athena Diagnostics

Oct 18, 2017

- -

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_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.2
Dann	Benign	0.97
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.75	D
MutationTaster	Benign	1.0	D;N;N;N
Vest4		0.24
ClinPred		0.011	T
GERP RS		0.044

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: rs140060332; hg19: chr16-79245696;