ATG7
protein-codingautophagy related 7, the group of Ubiquitin like modifier activating enzymes|Autophagy related
Gene summary
This gene encodes an E1-like activating enzyme that is essential for autophagy and cytoplasmic to vacuole transport. The encoded protein is also thought to modulate p53-dependent cell cycle pathways during prolonged metabolic stress. It has been associated with multiple functions, including axon membrane trafficking, axonal homeostasis, mitophagy, adipose differentiation, and hematopoietic stem cell maintenance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
- APG7L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~285.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030323
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030323
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0030323
Submitter: ClinGen
The relationship between the ATG7 gene and spinocerebellar ataxia, autosomal recessive 31 (SCAR31), was evaluated using the ClinGen Clinical Validity Framework as of July 18, 2022. ATG7 encodes autophagy-related 7 protein, a ubiquitin-activating enzyme E1 involved in cellular autophagy (i.e., cellular degradation and recycling of organelles and proteins) via binding ATG12 (ubiquitin-like molecule) to form a complex that mediates membrane fusion in autophagy (PMID: 11096062). ATG7 is deficient among patients with SCAR31, as reflected by severely diminished levels of ATG7 protein (measured via immunoblot analysis) in muscle cells and fibroblasts among patients with SCAR31 (PMID: 34161705), and SCAR31 patients show impaired autophagy, as reflected by accumulation of the autophagic substrate p62 and reduced autophagic flux (as reflected by reduced levels of the autophagosomal marker LC3-II) in patient fibroblasts (PMID: 34161705). The disease mechanism of SCAR31 is loss of function. SCAR31 was first reported in 2021 (PMID: 34161705) and this was also the first report of biallelic variants in ATG7 among patients with SCAR31 (PMID: 34161705). In this report, a total of nine different ATG7 variants were noted among 12 individuals from five families and the variants segregated with disease in all families. The variants reported included nonsense, splice-site, and missense variants, and for eight of the nine variants, direct functional assessments demonstrated that they impaired wild-type protein function. To date, this first report (PMID: 34161705) appears to be the only report of biallelic ATG7 variants among patients with SCAR31. In addition to the case-level (genetic) evidence (6.1 points total), there is also experimental evidence supporting the relationship between SCAR31 and ATG7 (6 points total). Experimental evidence for the relationship between ATG5 and SCAR31 includes the biochemical function of the gene product (autophagy-related 7 protein) being consistent with the impaired autophagy found in individuals with SCAR31 (PMID: 34161705), the biochemical and clinical features of a ATG7 knockout mouse model (PMID:16625205), and rescue autophagic activity in (ATG7-deficient) patient fibroblasts via reintroduction of wild-type ATG7 (PMID: 34161705). In sum, based on the strength of the evidence from the published report to date, the association between ATG7 and SCAR31 reaches the score range for Definitive. However, to our knowledge, only a single report of human cases exists (PMID: 34161705); thus, per the ClinGen Gene Curation, the ATG7-SCAR31 association can currently be classified as Strong, and can be classified as Definitive once there are additional follow-up publications to demonstrate that the association has been replicated over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 2, 2022 (SOP v9).
Inheritance Pattern: AR
Disease ID:MONDO:0030323
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030323
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; 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 ATG7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001349232.2. 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 | 1 | 11 | 1 | 13 | ||
| missense | 4 | 94 | 9 | 107 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 12 | 14 | ||
| Total | 6 | 2 | 107 | 20 | 1 | 136 |
Highest pathogenic variant AF is 0.00023213378
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001336161.1 | 18 | MANE Select | |
| Ensembl | ENSP00000510336.1 | 18 | MANE Select | |
| RefSeq | NP_001129503.2 | 17 | Standard | |
| RefSeq | NP_001138384.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atg7 | Danio rerio | Structure: cell Quality: decreased process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Autophagy - animal - Homo sapiens (human)
- Autophagy - other - Homo sapiens (human)
- Ferroptosis - Homo sapiens (human)
- Nanoparticle triggered autophagic cell death
- Senescence and Autophagy in Cancer
Biological Process
- autophagosome assembly
- autophagy of mitochondrion
- cellular protein modification process
- protein lipidation
- C-terminal protein lipidation
Molecular Function
- ubiquitin activating enzyme activity
- protein binding
- transcription factor binding
- Atg12 activating enzyme activity
- Atg8 activating enzyme activity
Cellular Component
- phagophore assembly site
- extracellular region
- cytoplasm
- cytosol
- axoneme
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354449
- Coding exons
- 18
- Length
- 285145
- Individuals with no LoFs
- 125658
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 90
- Defined
- 125748
- p
- 0.000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.37 | 313 | 389 | 0.805 | 0.0000207 | 4612 |
| Missense (PolyPhen) | 77 | 104.71 | 0.73538 | 1192 | ||
| Synonymous | 0.114 | 143 | 145 | 0.988 | 0.00000794 | 1355 |
| Loss of Function | 1.86 | 23 | 34.8 | 0.660 | 0.00000156 | 455 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00074 | 0.00074 | rare |
| Latino/Admixed American | 0.00036 | 0.00035 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00046 | 0.00046 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E1-like activating enzyme involved in the 2 ubiquitin- like systems required for cytoplasm to vacuole transport (Cvt) and autophagy. Activates ATG12 for its conjugation with ATG5 as well as the ATG8 family proteins for their conjugation with phosphatidylethanolamine. Both systems are needed for the ATG8 association to Cvt vesicles and autophagosomes membranes. Required for autophagic death induced by caspase-8 inhibition. Required for mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Modulates p53/TP53 activity to regulate cell cycle and survival during metabolic stress. Plays also a key role in the maintenance of axonal homeostasis, the prevention of axonal degeneration, the maintenance of hematopoietic stem cells, the formation of Paneth cell granules, as well as in adipose differentiation. {ECO:0000269|PubMed:11096062, ECO:0000269|PubMed:16303767, ECO:0000269|PubMed:22170151}.;
Recessive Scores
- pRec
- 0.173
Intolerance Scores
- LoFtool
- 0.902
- RVIS EVS
- -0.51
- RVIS percentile EVS
- 21.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.448
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |