rs786201017
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_016077.5(PTRH2):c.269_270del(p.Ala90GlyfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PTRH2
NM_016077.5 frameshift
NM_016077.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.80
Genes affected
PTRH2 (HGNC:24265): (peptidyl-tRNA hydrolase 2) The protein encoded by this gene is a mitochondrial protein with two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. In vitro assays suggest that this protein possesses peptidyl-tRNA hydrolase activity, to release the peptidyl moiety from tRNA, thereby preventing the accumulation of dissociated peptidyl-tRNA that could reduce the efficiency of translation. This protein also plays a role regulating cell survival and death. It promotes survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), but also promotes apoptosis in cells that have lost their attachment to the ECM, a process called anoikos. After loss of cell attachment to the ECM, this protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes caspase-independent apoptosis through interactions with transcriptional regulators. This gene has been implicated in the development and progression of tumors, and mutations in this gene have been associated with an infantile multisystem neurologic, endocrine, and pancreatic disease (INMEPD) characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreas insufficiency (PMID: 25574476). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.502 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-59697708-CAG-C is Pathogenic according to our data. Variant chr17-59697708-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 183428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTRH2 | NM_016077.5 | c.269_270del | p.Ala90GlyfsTer13 | frameshift_variant | 2/2 | ENST00000393038.3 | |
PTRH2 | NM_001015509.3 | c.272_273del | p.Ala91GlyfsTer13 | frameshift_variant | 3/3 | ||
PTRH2 | XM_011524887.3 | c.269_270del | p.Ala90GlyfsTer13 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTRH2 | ENST00000393038.3 | c.269_270del | p.Ala90GlyfsTer13 | frameshift_variant | 2/2 | 1 | NM_016077.5 | P4 | |
PTRH2 | ENST00000409433.2 | c.272_273del | p.Ala91GlyfsTer13 | frameshift_variant | 3/3 | 1 | A1 | ||
PTRH2 | ENST00000470557.2 | c.269_270del | p.Ala90GlyfsTer13 | frameshift_variant | 1/1 | P4 | |||
PTRH2 | ENST00000587935.1 | n.45+9661_45+9662del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Mar 19, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | PTRH2: PVS1:Strong, PM2, PM3, PP4, PS4:Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at