chr16-78099797-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_016373.4(WWOX):c.19G>A(p.Ala7Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000747 in 1,565,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 0 hom. )
Consequence
WWOX
NM_016373.4 missense
NM_016373.4 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 7.16
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23368603).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.19G>A | p.Ala7Thr | missense_variant | 1/9 | ENST00000566780.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.19G>A | p.Ala7Thr | missense_variant | 1/9 | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000566 AC: 10AN: 176566Hom.: 0 AF XY: 0.0000733 AC XY: 7AN XY: 95462
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GnomAD4 exome AF: 0.0000743 AC: 105AN: 1413792Hom.: 0 Cov.: 31 AF XY: 0.0000586 AC XY: 41AN XY: 699724
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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 | Invitae | Jul 19, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 7 of the WWOX protein (p.Ala7Thr). This variant is present in population databases (rs371392600, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1424743). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
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
Benign
T;.;D;T;D;D;D;T
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
P;.;D;P;.;P;P;.
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at