PITRM1

protein-coding

pitrilysin metallopeptidase 1, the group of M16 metallopeptidases

Gene summary

The protein encoded by this gene is an ATP-dependent metalloprotease that degrades post-cleavage mitochondrial transit peptides. The encoded protein binds zinc and can also degrade amyloid beta A4 protein, suggesting a possible role in Alzheimer's disease. [provided by RefSeq, Dec 2016]

MANE transcript

NM_014889.4

Inheritance

ClinVar variants

P:4U:266B:157

Top phenotype

Spinocerebellar ataxia, autosomal recessive 30

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr10:3,137,728-3,172,841

External References & Databases

Ensembl (ENSG00000107959)

Transcript & Mutation Effects

hg38 • Region Span ~35.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia, autosomal recessive 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030318

Submitter: PanelApp Australia

spinocerebellar ataxia, autosomal recessive 30STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030318

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia, autosomal recessive 30LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030318

Submitter: Illumina

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive 30AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26697887; 29764912; 33835239

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PITRM1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 301

not providedTotal: 260

PITRM1-related disorderTotal: 25

Spinocerebellar ataxia, autosomal recessive 30Total: 7

Irido-corneo-trabecular dysgenesisTotal: 2

Cerebellar ataxiaTotal: 1

Infantile onset spinocerebellar ataxiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014889.4. 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			5 clinvar	103 clinvar	1 clinvar	109
missense		1 clinvar	245 clinvar	43 clinvar	8 clinvar	297
nonsense		1 clinvar	3 clinvar	1 clinvar		5
start loss						0
frameshift	1 clinvar	1 clinvar	5 clinvar	1 clinvar		8
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	1	3	266	148	9	427

Highest pathogenic variant AF is 0.000043995213

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014889.4	RefSeq	NP_055704.2	27	MANE Select
ENST00000224949.9	Ensembl	ENSP00000224949.4	27	MANE Select
NM_001242307.2	RefSeq	NP_001229236.1	27	Standard
NM_001242309.1	RefSeq	NP_001229238.1	24	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

proteolysis
protein targeting to mitochondrion
protein processing
positive regulation of catalytic activity

Molecular Function

metalloendopeptidase activity
enzyme activator activity
metallopeptidase activity
zinc ion binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380989
Coding exons: 27
Length: 35084
Individuals with no LoFs: 124464
Homozygous LoFs: 0
Heterozygous LoFs: 184
Defined: 124648
p: 0.000738

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.837	653	596	1.10	0.0000349	6808
Missense (PolyPhen)		199	202.42	0.98308		2350
Synonymous	-2.68	302	248	1.22	0.0000172	1926
Loss of Function	1.93	40	55.5	0.721	0.00000272	657

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0024	0.0024	notable
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00090	0.00089	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00083	0.00082	rare
South Asian	0.00073	0.00072	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing (PubMed:10360838, PubMed:16849325, PubMed:19196155, PubMed:24931469). Has an ATP-independent activity (PubMed:16849325). Specifically cleaves peptides in the range of 5 to 65 residues (PubMed:19196155). Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference (PubMed:10360838, PubMed:19196155, PubMed:24931469). Degrades the transit peptides of mitochondrial proteins after their cleavage (PubMed:19196155). Also degrades other unstructured peptides (PubMed:19196155). It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion (PubMed:16849325, PubMed:24931469). It is a highly efficient protease, at least toward amyloid-beta protein 40 (PubMed:24931469). Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently (PubMed:24931469). {ECO:0000269|PubMed:10360838, ECO:0000269|PubMed:16849325, ECO:0000269|PubMed:19196155, ECO:0000269|PubMed:24931469}.;

Recessive Scores

pRec: 0.173

Intolerance Scores

LoFtool: 0.982
RVIS EVS: 3.22
RVIS percentile EVS: 99.36

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

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