10-99727157-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_078470.6(COX15):c.396-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_078470.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COX15 | ENST00000016171.6 | c.396-3C>G | splice_region_variant, intron_variant | Intron 3 of 8 | 1 | NM_078470.6 | ENSP00000016171.6 | |||
COX15 | ENST00000370483.9 | c.396-3C>G | splice_region_variant, intron_variant | Intron 3 of 8 | 1 | ENSP00000359514.5 | ||||
ENSG00000285932 | ENST00000649102.1 | n.396-86C>G | intron_variant | Intron 3 of 12 | ENSP00000497114.1 | |||||
CUTC | ENST00000493385.5 | n.309+4047G>C | intron_variant | Intron 2 of 4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251368Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135880
GnomAD4 exome AF: 0.000187 AC: 274AN: 1461720Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 117AN XY: 727180
GnomAD4 genome AF: 0.000112 AC: 17AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74436
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2025 | This sequence change falls in intron 3 of the COX15 gene. It does not directly change the encoded amino acid sequence of the COX15 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200910834, gnomAD 0.01%). This variant has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 12474143). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as C447-3G. ClinVar contains an entry for this variant (Variation ID: 280009). Studies have shown that this variant alters COX15 gene expression (PMID: 12474143). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 32232962, 29431110, 12474143) - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2017 | - - |
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 19, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2003 | - - |
Leigh syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2024 | Variant summary: COX15 c.396-3C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 3' acceptor site and one predicts the variant weakens the canonical 3' acceptor site. One publication reports experimental evidence that this variant indeed affects mRNA splicing, causing a frameshift and premature truncation as a result of the skipping of exon 4 (Antonicka_2003). The variant allele was found at a frequency of 7.6e-05 in 251368 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in COX15 causing Leigh Syndrome (7.6e-05 vs 0.0013), allowing no conclusion about variant significance. c.396-3C>G has been reported in the literature in the compound heterozygous state together with a pathogenic variant in an individual with isolated cytochrome c oxidase (COX) deficiency and early onset, fatal hypertrophic cardiomyopathy (Antonicka_2003). This individual had reduced COX activity, particularly in heart tissue, and overexpression of COX15 in cultured fibroblasts restored activity to approximately 60% of normal (Antonicka_2003). Altogether these data suggest the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 12474143). ClinVar contains an entry for this variant (Variation ID: 280009). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at