rs200019508
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting
The NM_016373.4(WWOX):c.1078G>A(p.Val360Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,614,168 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 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
WWOX
NM_016373.4 missense
NM_016373.4 missense
Scores
2
4
10
Clinical Significance
Conservation
PhyloP100: 6.16
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 1 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_016373.4
PM2
?
Very rare variant in population databases, with high coverage;
BP4
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Computational evidence support a benign effect (MetaRNN=0.11607632).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000125 (19/152276) while in subpopulation AMR AF= 0.000915 (14/15306). AF 95% confidence interval is 0.000552. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.1078G>A | p.Val360Met | missense_variant | 9/9 | ENST00000566780.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.1078G>A | p.Val360Met | missense_variant | 9/9 | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000883 AC: 22AN: 249266Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135324
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GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461892Hom.: 0 Cov.: 87 AF XY: 0.0000605 AC XY: 44AN XY: 727246
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GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74452
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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 | Invitae | Aug 16, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 360 of the WWOX protein (p.Val360Met). This variant is present in population databases (rs200019508, 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: 540230). 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 16, 2023 | The c.1078G>A (p.V360M) alteration is located in exon 9 (coding exon 9) of the WWOX gene. This alteration results from a G to A substitution at nucleotide position 1078, causing the valine (V) at amino acid position 360 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;N;N
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
ClinPred
T
GERP RS
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