rs368670215
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016373.4(WWOX):c.958G>A(p.Ala320Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
WWOX
NM_016373.4 missense
NM_016373.4 missense
Scores
1
12
5
Clinical Significance
Conservation
PhyloP100: 6.36
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.958G>A | p.Ala320Thr | missense_variant | 8/9 | ENST00000566780.6 | |
WWOX | NM_001291997.2 | c.619G>A | p.Ala207Thr | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.958G>A | p.Ala320Thr | missense_variant | 8/9 | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249574Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135394
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727246
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | Invitae | Apr 04, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 320 of the WWOX protein (p.Ala320Thr). This variant is present in population databases (rs368670215, gnomAD 0.03%). 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: 410085). 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: "Benign"; 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2022 | The c.958G>A (p.A320T) alteration is located in exon 8 (coding exon 8) of the WWOX gene. This alteration results from a G to A substitution at nucleotide position 958, causing the alanine (A) at amino acid position 320 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
M;M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
P;.;.
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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