rs117065412

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000566780.6(WWOX):​c.1238C>A​(p.Ser413Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,614,074 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S413C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 17 hom., cov: 33)
Exomes 𝑓: 0.019 ( 289 hom. )

Consequence

WWOX
ENST00000566780.6 missense

Scores

1
3
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.66
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.003261149).
BP6
Variant 16-79211789-C-A is Benign according to our data. Variant chr16-79211789-C-A is described in ClinVar as [Benign]. Clinvar id is 241099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-79211789-C-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2088/152302) while in subpopulation NFE AF= 0.0215 (1462/68006). AF 95% confidence interval is 0.0206. There are 17 homozygotes in gnomad4. There are 977 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WWOXNM_016373.4 linkuse as main transcriptc.1238C>A p.Ser413Tyr missense_variant 9/9 ENST00000566780.6 NP_057457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WWOXENST00000566780.6 linkuse as main transcriptc.1238C>A p.Ser413Tyr missense_variant 9/91 NM_016373.4 ENSP00000457230 P1Q9NZC7-1

Frequencies

GnomAD3 genomes
AF:
0.0137
AC:
2087
AN:
152184
Hom.:
17
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00350
Gnomad AMI
AF:
0.0570
Gnomad AMR
AF:
0.0151
Gnomad ASJ
AF:
0.0216
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00600
Gnomad FIN
AF:
0.00565
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0215
Gnomad OTH
AF:
0.0120
GnomAD3 exomes
AF:
0.0128
AC:
3186
AN:
248544
Hom.:
32
AF XY:
0.0132
AC XY:
1786
AN XY:
135062
show subpopulations
Gnomad AFR exome
AF:
0.00267
Gnomad AMR exome
AF:
0.00696
Gnomad ASJ exome
AF:
0.0210
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00621
Gnomad FIN exome
AF:
0.00661
Gnomad NFE exome
AF:
0.0204
Gnomad OTH exome
AF:
0.0113
GnomAD4 exome
AF:
0.0187
AC:
27391
AN:
1461772
Hom.:
289
Cov.:
89
AF XY:
0.0185
AC XY:
13443
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00266
Gnomad4 AMR exome
AF:
0.00742
Gnomad4 ASJ exome
AF:
0.0205
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00632
Gnomad4 FIN exome
AF:
0.00781
Gnomad4 NFE exome
AF:
0.0219
Gnomad4 OTH exome
AF:
0.0175
GnomAD4 genome
AF:
0.0137
AC:
2088
AN:
152302
Hom.:
17
Cov.:
33
AF XY:
0.0131
AC XY:
977
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00349
Gnomad4 AMR
AF:
0.0150
Gnomad4 ASJ
AF:
0.0216
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00622
Gnomad4 FIN
AF:
0.00565
Gnomad4 NFE
AF:
0.0215
Gnomad4 OTH
AF:
0.0118
Alfa
AF:
0.0182
Hom.:
46
Bravo
AF:
0.0134
TwinsUK
AF:
0.0275
AC:
102
ALSPAC
AF:
0.0246
AC:
95
ESP6500AA
AF:
0.00255
AC:
10
ESP6500EA
AF:
0.0218
AC:
181
ExAC
AF:
0.0127
AC:
1535
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.0195
EpiControl
AF:
0.0204

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 31, 2017- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024WWOX: BP4, BS1, BS2 -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJan 14, 2016This 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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Developmental and epileptic encephalopathy, 28 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Autosomal recessive spinocerebellar ataxia 12 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.060
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.57
T;T
MetaRNN
Benign
0.0033
T;T
MetaSVM
Benign
-0.79
T
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.51
N;N
REVEL
Uncertain
0.33
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.019
D;D
Polyphen
0.070
B;B
Vest4
0.32
ClinPred
0.020
T
GERP RS
5.7
Varity_R
0.24
gMVP
0.38

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: rs117065412; hg19: chr16-79245686; COSMIC: COSV68371157; COSMIC: COSV68371157; API