PTRH2

protein-coding

peptidyl-tRNA hydrolase 2, the group of Cilia and flagella associated

Gene summary

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]

MANE transcript

NM_016077.5

Inheritance

ClinVar variants

P:11U:23B:8

Top phenotype

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr17:59,674,636-59,707,626

External References & Databases

Ensembl (ENSG00000141378)

Transcript & Mutation Effects

hg38 • Region Span ~33.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:8000012

Submitter: G2P

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:8000012

Submitter: Labcorp Genetics (formerly Invitae)

infantile multisystem neurologic-endocrine-pancreatic diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014554

Submitter: Orphanet

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:8000012

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Gastrointestinal

Rationale: The condition has been described as including exocrine pancreatic insufficiency, among other manifestatons, and awareness may allow medical management

Refs: 25558065; 25574476; 27129381; 28328138; 33092935

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTRH2 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 19

not providedTotal: 14

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1Total: 9

not specifiedTotal: 6

PTRH2-related disorderTotal: 4

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onsetTotal: 2

Cerebellar ataxiaTotal: 1

Inborn errors of metabolismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016077.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				6 clinvar		6
missense	1 clinvar	1 clinvar	21 clinvar	2 clinvar		25
nonsense	1 clinvar	5 clinvar				6
start loss						0
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)						0
Total	3	8	23	8	0	42

Highest pathogenic variant AF is 0.000010945036

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016077.5	RefSeq	NP_057161.1	1	MANE Select
ENST00000393038.3	Ensembl	ENSP00000376758.2	1	MANE Select
NM_001015509.3	RefSeq	NP_001015509.1	2	Standard
ENST00000409433.2	Ensembl	ENSP00000387180.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis Modulation and Signaling
Post-translational protein modification
Metabolism of proteins
Ub-specific processing proteases
Deubiquitination

Biological Process

apoptotic process
negative regulation of gene expression
positive regulation of anoikis
negative regulation of anoikis

Molecular Function

aminoacyl-tRNA hydrolase activity
protein binding

Cellular Component

mitochondrion
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000470557
Coding exons: 1
Length: 32991
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.427	83	94.7	0.876	0.00000474	1158
Missense (PolyPhen)		22	33.501	0.6567		404
Synonymous	-0.684	40	34.9	1.15	0.00000175	368
Loss of Function	0.280	5	5.72	0.874	3.79e-7	69

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The natural substrate for this enzyme may be peptidyl- tRNAs which drop off the ribosome during protein synthesis. {ECO:0000250}.;
Disease: DISEASE: Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset (IMNEPD) [MIM:616263]: A progressive multisystem disease characterized by a variety of neurologic, endocrine, and, in some patients, pancreatic features. Variable clinical symptoms include global developmental delay, hypotonia, hearing loss, ataxia, hyporeflexia, facial dysmorphism, hypothyroidism, and pancreatic insufficiency. {ECO:0000269|PubMed:25558065, ECO:0000269|PubMed:25574476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0903

Intolerance Scores

LoFtool: 0.264
RVIS EVS: 0.1
RVIS percentile EVS: 61.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium