12-123253769-T-TATCC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152269.5(MTRFR):c.96_99dupATCC(p.Pro34IlefsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). 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: 0.0000657 AC: 10AN: 152176Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251336Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135860
GnomAD4 exome AF: 0.0000999 AC: 146AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.0000921 AC XY: 67AN XY: 727246
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152176Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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The c.96_99dupATCC variant in the C12orf65 gene has been reported previously in association with optic atrophy and respiratory chain defects in several unrelated individuals who were homozygous for c.96_99dupATCC or compound heterozygous for c.96_99dupATCC and another frame shift variant in C12orf65 (Taylor et al., 2014; Heidary et al., 2014; Pyle et al., 2014). The duplication causes a frameshift starting with codon Proline 34, changes this amino acid to a Isoleucine residue and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Pro34IlefsX25. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Combined oxidative phosphorylation defect type 7;C3539506:Hereditary spastic paraplegia 55 Pathogenic:1
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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.Pro34Ilefs*25) in the C12orf65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C12orf65 are known to be pathogenic (PMID: 20598281, 24424123). This variant is present in population databases (rs765675424, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Behr’s syndrome (PMID: 24284555, 25058219, 26380172, 28251916). 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: 214192). 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