10-99716419-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_078470.6(COX15):āc.1030T>Cā(p.Ser344Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,970 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_078470.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COX15 | ENST00000016171.6 | c.1030T>C | p.Ser344Pro | missense_variant | Exon 8 of 9 | 1 | NM_078470.6 | ENSP00000016171.6 | ||
ENSG00000285932 | ENST00000649102.1 | n.*389T>C | non_coding_transcript_exon_variant | Exon 8 of 13 | ENSP00000497114.1 | |||||
ENSG00000285932 | ENST00000649102.1 | n.*389T>C | 3_prime_UTR_variant | Exon 8 of 13 | ENSP00000497114.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461720Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727180
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1AN XY: 74430
ClinVar
Submissions by phenotype
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 Pathogenic:2
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not provided Pathogenic:1
Reported with a second COX15 variant, phase unknown, in unrelated patients with COX15-related features referred for genetic testing at GeneDx and in published literature (PMID: 15863660, 39113384); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33238568, 34426522, 22310368, 26940873, 33746038, 33171185, 21680271, 32232962, 34428995, 26959537, 39113384, 15863660) -
not specified Uncertain:1
Variant summary: COX15 c.1030T>C (p.Ser344Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250864 control chromosomes (gnomAD). c.1030T>C has been reported in the literature as a compound heterozygous genotype together with a truncating variant in an individual affected with Leigh Syndrome (Bugiani_2005). Biochemical assays showed an isolated COX deficiency in both skeletal muscle and cultured fibroblasts from this patient (42% and 22% residual activity compared to controls, respectively), suggesting the variant impairs protein function (Bugiani_2005). These data suggest the variant may be associated with Leigh syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 15863660, 31102535). ClinVar contains an entry for this variant (Variation ID: 40258). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at