PAM16
protein-codingpresequence translocase associated motor 16, the group of TIM23 complex
Gene summary
This gene encodes a mitochondrial protein involved in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. This protein also plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis. Mutations in this gene cause Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, an early lethal skeletal dysplasia characterized by short stature, developmental delay and other skeletal abnormalities. [provided by RefSeq, May 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013223
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013223
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013223
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013223
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PAM16 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016069.11. 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 | 14 | 14 | ||||
| missense | 2 | 25 | 27 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 0 | 25 | 14 | 0 | 41 |
Highest pathogenic variant AF is 6.843512e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057153.8 | 5 | MANE Select | |
| Ensembl | ENSP00000315693.3 | 5 | MANE Select | |
| Ensembl | ENSP00000460434.1 | 2 | Standard | |
| Ensembl | ENSP00000460708.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism of proteins
- Mitochondrial protein import
Biological Process
- ossification
- protein import into mitochondrial matrix
- negative regulation of ATPase activity
- negative regulation of release of cytochrome c from mitochondria
- negative regulation of apoptotic DNA fragmentation
Molecular Function
- protein binding
Cellular Component
- PAM complex, Tim23 associated import motor
- TIM23 mitochondrial import inner membrane translocase complex
- mitochondrial matrix
- extrinsic component of mitochondrial inner membrane
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318059
- Coding exons
- 5
- Length
- 24059
- Individuals with no LoFs
- 125499
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125506
- p
- 0.0000279
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.511 | 94 | 81.1 | 1.16 | 0.00000540 | 793 |
| Missense (PolyPhen) | 25 | 25.548 | 0.97856 | 284 | ||
| Synonymous | 0.0118 | 33 | 33.1 | 0.997 | 0.00000214 | 244 |
| Loss of Function | 1.82 | 2 | 7.32 | 0.273 | 3.96e-7 | 81 |
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 | 0.00011 | 0.00011 | rare |
| Finnish | 0.000050 | 0.000046 | rare |
| European (Non-Finnish) | 0.000038 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulates ATP-dependent protein translocation into the mitochondrial matrix. Inhibits DNAJC19 stimulation of HSPA9/Mortalin ATPase activity. {ECO:0000269|PubMed:20053669}.;
- Disease
- DISEASE: Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type (SMDMDM) [MIM:613320]: An autosomal recessive disease characterized by pre- and postnatal short stature, developmental delay, dysmorphic facial appearance, narrow chest, prominent abdomen, platyspondyly, and short limbs. {ECO:0000269|PubMed:24786642}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- RVIS EVS
- 0.39
- RVIS percentile EVS
- 75.87
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |