chr16-78099785-G-A
Position:
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
NM_016373.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 8.94
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 |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.7G>A | p.Ala3Thr | missense_variant | 1/9 | ENST00000566780.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.7G>A | p.Ala3Thr | missense_variant | 1/9 | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.13e-7 AC: 1AN: 1403358Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 693546
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1403358
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
693546
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 28, 2017 | This 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 submitter | clinical testing | GeneDx | Jun 24, 2020 | Not 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;N;N;.;N;N;N
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;.;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
D;.;D;D;.;D;D;.
Vest4
MutPred
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
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at