rs376293017

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_ModerateBP6_Very_Strong

The ENST00000402655.6(WWOX):​c.532G>A​(p.Gly178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,614,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G178D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

WWOX
ENST00000402655.6 missense

Scores

1
14

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.254
Variant links:
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:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 9 uncertain in ENST00000402655.6
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.094396144).
BP6
Variant 16-79211730-G-A is Benign according to our data. Variant chr16-79211730-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 382145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WWOXNM_016373.4 linkuse as main transcriptc.1179G>A p.Thr393Thr synonymous_variant 9/9 ENST00000566780.6 NP_057457.1 Q9NZC7-1A0A411HBC7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WWOXENST00000566780.6 linkuse as main transcriptc.1179G>A p.Thr393Thr synonymous_variant 9/91 NM_016373.4 ENSP00000457230.1 Q9NZC7-1

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152200
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
249514
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135394
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000167
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000168
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.000251
AC:
367
AN:
1461880
Hom.:
0
Cov.:
88
AF XY:
0.000232
AC XY:
169
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000308
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152200
Hom.:
1
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000131
Hom.:
0
Bravo
AF:
0.000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000360
AC:
3
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 04, 2017This 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. -
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
2.7
DANN
Benign
0.97
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.25
T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.094
T
MetaSVM
Benign
-1.1
T
PROVEAN
Benign
-0.35
N
REVEL
Benign
0.047
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.091
T
Polyphen
0.85
P
Vest4
0.094
MVP
0.57
ClinPred
0.069
T
GERP RS
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376293017; hg19: chr16-79245627; API