rs576462794
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152269.5(MTRFR):βc.210delAβ(p.Gly72AlafsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_152269.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152190Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000175 AC: 44AN: 251348Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135874
GnomAD4 exome AF: 0.000224 AC: 327AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160AN XY: 727244
GnomAD4 genome AF: 0.000158 AC: 24AN: 152308Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74484
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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PP1, PM2, PM3, PVS1 -
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MTRFR: PVS1, PM2, PM3 -
Frameshift variant predicted to result in protein truncation, as the last 95 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 20598281, 24284555, 27858754, 30609409, 36344503) -
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Combined oxidative phosphorylation defect type 7 Pathogenic:4Other:1
Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) 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. One study of C12orf65 mRNA from a homozygous patient showed the level of the C12orf65 mRNA was not significantly reduced, suggesting that nonsense-mediated mRNA decay does not contribute to the loss of function of the C12orf65 gene product (Antonicka_2010). Truncations downstream of this position have been reported with various Mitochondrial disorders in HGMD. The variant allele was found at a frequency of 0.00018 in 251348 control chromosomes. c.210delA has been reported in the literature in multiple individuals affected mitochondrial disorders including Leigh syndrome, optic atrophy, and ophthalmoplegia (examples: Antonicka_2010, Heidary_2014, Wesolowska_2015, Schon_2021). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The C12orf65 c.210delA (p.Gly72AlafsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly72AlafsTer13 variant has been reported in three studies and is found in four probands with combined oxidative phosphorylation deficiency (COXPD) including in two in a homozygous state and in two siblings in a compound heterozygous state (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00032 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly72AlafsTer13 variant resulted in reduced complex IV activity and reduced quantities of complex I, IV, and V in proband fibroblasts (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Based on the potential impact of frameshift variants and available evidence, the p.Gly72AlafsTer13 variant is classified as pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Variant classified as Pathogenic and reported on 10-10-2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
The p.Gly72AlafsX13 variant in C12orf65 has been reported in 2 homozygous and 1 compound heterozygous probands with clinical features of combined oxidative phos phorylation deficiency type 7 (COXPD7) and segregated with disease in one additi onal affected sibling (Antonika 2010, Heidary 2013, Wesolowska 2015). This varia nt has also been identified in 1/8254 of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs57646274). This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 72 and leads to a premature termination codon 1 3 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Biallelic loss of function of the C12orf65 gene has been a ssociated with COXPD7. In summary, this variant meets criteria to be classified as pathogenic for COXPD7 in an autosomal recessive manner based upon its occurr ence in affected individuals and predicted functional impact. -
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Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gly72Alafs*13) in the C12orf65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the C12orf65 protein. This variant is present in population databases (rs576462794, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of C12orf65-related conditions (PMID: 20598281, 24284555, 27858754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at