NAE1
protein-codingNEDD8 activating enzyme E1 subunit 1, the group of Ubiquitin like modifier activating enzymes
Gene summary
The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface protein with signal-transducing properties, and it is thought to play a role in the pathogenesis of Alzheimer's disease. In addition, the encoded protein can form a heterodimer with UBE1C and bind and activate NEDD8, a ubiquitin-like protein. This protein is required for cell cycle progression through the S/M checkpoint. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
- APPBP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~70.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0859361
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0859361
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0859361
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0859361
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; 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 NAE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003905.4. 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 | 3 | 3 | 6 | |||
| missense | 3 | 1 | 66 | 2 | 72 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 12 | 12 | ||||
| Total | 3 | 1 | 81 | 5 | 0 | 90 |
Highest pathogenic variant AF is 0.000005577024
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003896.1 | 20 | MANE Select | |
| Ensembl | ENSP00000290810.3 | 20 | MANE Select | |
| RefSeq | NP_001018169.1 | 20 | Standard | |
| RefSeq | NP_001018170.1 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Alzheimer,s disease - Homo sapiens (human)
- Alzheimers Disease
- Post-translational protein modification
- Metabolism of proteins
- Neddylation
Biological Process
- signal transduction
- protein modification by small protein conjugation
- mitotic DNA replication checkpoint
- regulation of apoptotic process
- regulation of neuron apoptotic process
Molecular Function
- protein binding
- NEDD8 activating enzyme activity
- ubiquitin protein ligase binding
- protein heterodimerization activity
Cellular Component
- cytoplasm
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000290810
- Coding exons
- 20
- Length
- 70382
- Individuals with no LoFs
- 125697
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 125748
- p
- 0.000203
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.09 | 218 | 268 | 0.813 | 0.0000130 | 3498 |
| Missense (PolyPhen) | 35 | 76.376 | 0.45826 | 995 | ||
| Synonymous | 1.04 | 79 | 91.6 | 0.862 | 0.00000456 | 946 |
| Loss of Function | 1.85 | 26 | 38.3 | 0.678 | 0.00000216 | 454 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00016 | 0.00014 | rare |
| Ashkenazi Jewish | 0.0010 | 0.00099 | notable |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00029 | 0.00026 | rare |
| Other | 0.0010 | 0.00098 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. {ECO:0000269|PubMed:10207026, ECO:0000269|PubMed:10722740, ECO:0000269|PubMed:12740388}.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- LoFtool
- 0.931
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 34.6
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.854
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |