chr13-23805971-GC-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005932.4(MIPEP):c.1826del(p.Gly609AlafsTer86) variant causes a frameshift change. The variant allele was found at a frequency of 0.000105 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
MIPEP
NM_005932.4 frameshift
NM_005932.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.88
Genes affected
MIPEP (HGNC:7104): (mitochondrial intermediate peptidase) The product of this gene performs the final step in processing a specific class of nuclear-encoded proteins targeted to the mitochondrial matrix or inner membrane. This protein is primarily involved in the maturation of oxidative phosphorylation (OXPHOS)-related proteins. This gene may contribute to the functional effects of frataxin deficiency and the clinical manifestations of Friedreich ataxia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MIPEP | NM_005932.4 | c.1826del | p.Gly609AlafsTer86 | frameshift_variant | 16/19 | ENST00000382172.4 | |
MIPEP | XM_011535097.3 | c.1640del | p.Gly547AlafsTer86 | frameshift_variant | 16/19 | ||
MIPEP | XM_011535098.4 | c.1826del | p.Gly609AlafsTer53 | frameshift_variant | 16/17 | ||
MIPEP | XM_047430368.1 | c.1640del | p.Gly547AlafsTer53 | frameshift_variant | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MIPEP | ENST00000382172.4 | c.1826del | p.Gly609AlafsTer86 | frameshift_variant | 16/19 | 1 | NM_005932.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251378Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135856
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GnomAD4 exome AF: 0.000107 AC: 157AN: 1461658Hom.: 0 Cov.: 30 AF XY: 0.000124 AC XY: 90AN XY: 727120
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change creates a premature translational stop signal (p.Gly609Alafs*86) in the MIPEP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 105 amino acid(s) of the MIPEP protein. This variant is present in population databases (rs751101220, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MIPEP-related conditions. ClinVar contains an entry for this variant (Variation ID: 2183775). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | Frameshift variant predicted to result in protein truncation, as the last 105 amino acids are replaced with 85 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2022 | Not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at