chr16-78099785-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016373.4(WWOX):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

WWOX
NM_016373.4 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.94
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WWOXNM_016373.4 linkuse as main transcriptc.7G>A p.Ala3Thr missense_variant 1/9 ENST00000566780.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WWOXENST00000566780.6 linkuse as main transcriptc.7G>A p.Ala3Thr missense_variant 1/91 NM_016373.4 P1Q9NZC7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.13e-7
AC:
1
AN:
1403358
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
693546
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 28, 2017This sequence change replaces alanine with threonine at codon 3 of the WWOX protein (p.Ala3Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "DELETERIOUS"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class 0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a WWOX-related disease. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 24, 2020Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;T;.;.;T;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.48
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.079
D
MutationAssessor
Benign
0.69
N;.;N;N;.;N;N;N
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.91
N;.;N;N;N;N;N;N
REVEL
Benign
0.27
Sift
Uncertain
0.011
D;.;D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;D;.;D;D;.
Vest4
0.67
MutPred
0.24
Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);Gain of phosphorylation at A3 (P = 0.0475);
MVP
0.97
ClinPred
0.99
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.32
gMVP
0.26

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: rs1336300148; hg19: chr16-78133682; API