NM_078470.6:c.452C>G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_078470.6(COX15):c.452C>G(p.Ser151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00033 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_078470.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COX15 | ENST00000016171.6 | c.452C>G | p.Ser151* | stop_gained | Exon 4 of 9 | 1 | NM_078470.6 | ENSP00000016171.6 | ||
COX15 | ENST00000370483.9 | c.452C>G | p.Ser151* | stop_gained | Exon 4 of 9 | 1 | ENSP00000359514.5 | |||
ENSG00000285932 | ENST00000649102.1 | n.396-27C>G | intron_variant | Intron 3 of 12 | ENSP00000497114.1 | |||||
CUTC | ENST00000493385.5 | n.309+3988G>C | intron_variant | Intron 2 of 4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000283 AC: 43AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000251 AC: 63AN: 251470Hom.: 0 AF XY: 0.000272 AC XY: 37AN XY: 135912
GnomAD4 exome AF: 0.000335 AC: 490AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 244AN XY: 727238
GnomAD4 genome AF: 0.000283 AC: 43AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74348
ClinVar
Submissions by phenotype
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 Pathogenic:2
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not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Ser151*) in the COX15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COX15 are known to be pathogenic (PMID: 15863660, 21412973). This variant is present in population databases (rs149718203, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 15863660, 21412973, 33746038). This variant is also known as 503C>G (H152X). ClinVar contains an entry for this variant (Variation ID: 496238). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21412973, 22310368, 33171185, 32232962, 31345219, 15863660, 33746038) -
Leigh syndrome Pathogenic:1
Variant summary: COX15 c.452C>G (p.Ser151X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00025 in 251510 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COX15 causing Leigh Syndrome (0.00025 vs 0.0013), allowing no conclusion about variant significance. c.452C>G has been reported in the literature in individuals affected with Leigh Syndrome and subsequently cited by others (example, Bugiani_2005, Invernizzi_2012, Alfadhel_2011, Halperin_2020, Miryounesi_2016, de Oliveira_2021). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal complex IV activity in patient derived muscle and fibroblast samples (Bugiani 2005, Alfadhel 2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
COX15-related disorder Pathogenic:1
The COX15 c.452C>G variant is predicted to result in premature protein termination (p.Ser151*). This variant has been reported in the compound heterozygous state in individuals with COX15-related disease (Bugiani et al. 2005. PubMed ID: 15863660; Alfadhel et al. 2011. PubMed ID: 21412973; Galvão de Oliveira et al. 2021. PubMed ID: 33746038). This variant is reported in 0.051% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in COX15 are expected to be pathogenic. This variant is interpreted as pathogenic. -
See cases Pathogenic:1
ACMG classification criteria: PVS1, PS4, PM2, PM3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at