IFNAR1
protein-codinginterferon alpha and beta receptor subunit 1, the group of Interferon receptors
Gene summary
The protein encoded by this gene is a type I membrane protein that forms one of the two chains of a receptor for interferons alpha and beta. Binding and activation of the receptor stimulates Janus protein kinases, which in turn phosphorylate several proteins, including STAT1 and STAT2. The protein belongs to the type II cytokine receptor family and functions as an antiviral factor. [provided by RefSeq, Jul 2020]
- IFNAR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~35.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030970
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030970
Submitter: ClinGen
*IFNAR1* was first reported in relation to autosomal recessive immunodeficiency 106, susceptibility to viral infections in 2019 (Hernandez N, et al., 2019, PMID: 31270247). *IFNAR1* encodes one of the 2 chains of the receptor of type I interferons. The predicted effect of *IFNAR1* deficiency is to prevent signaling and downstream functional responses to type I interferons but leave intact responses to type II and III. *IFNAR1* deficiency predisposes to disease following live attenuated viral vaccine, but also to Herpes Simplex Encephalitis and severe COVID-19. Genetic evidence was included in this curation from 8 probands in 6 publications (PMIDs: 31270247, 32960813, 33252644, 32972995, 35091979, 35442418). The proposed mechanism of disease is loss of function and the nine reported variants include missense, splice site, nonsense, and full exon deletions. There is no in vivo evidence of susceptibility to viral infections in healthy carriers. Experimentally, this gene-disease relationship is supported by its function as a receptor of type I interferons (PMID: 2153461). Functional alteration in patient cells resulted in major defects in type I IFN signaling (PMIDs: 31270247, 32960813, 33252644, 32972995) and inability to surpress viral replication, which could be rescued with WT *IFNAR1* (PMIDs: 31270247, 33252644, 32972995). Additionally, a null mouse model recapitulates diesase with increased susceptibility to viral infection (PMID: 7479980). In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0030970
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: The condition involves increased risk of viral infections as well as adverse events related to live virus vaccination, and antiinfectious prophylaxis, early and aggressive treatment of infections, and consideration of vaccination regimens may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IFNAR1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000629.3. 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 | 83 | 2 | 88 | ||
| missense | 140 | 14 | 2 | 156 | ||
| nonsense | 3 | 3 | 4 | 10 | ||
| start loss | 0 | |||||
| frameshift | 9 | 1 | 3 | 13 | ||
| splice donor/acceptor (+/-2bp) | 7 | 12 | 19 | |||
| Total | 12 | 11 | 162 | 97 | 4 | 286 |
Highest pathogenic variant AF is 0.00004650067
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000620.2 | 11 | MANE Select | |
| Ensembl | ENSP00000270139.3 | 11 | MANE Select | |
| RefSeq | NP_001371427.1 | 12 | Standard | |
| RefSeq | NP_001371428.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
- Necroptosis - Homo sapiens (human)
Biological Process
- JAK-STAT cascade
- response to virus
- cytokine-mediated signaling pathway
- response to lipopolysaccharide
- cellular response to interferon-alpha
Molecular Function
- cytokine receptor activity
- type I interferon receptor activity
- protein binding
- type I interferon binding
Cellular Component
- lysosome
- late endosome
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000270139
- Coding exons
- 11
- Length
- 35435
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125747
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.361 | 270 | 287 | 0.940 | 0.0000140 | 3690 |
| Missense (PolyPhen) | 65 | 73.552 | 0.88372 | 988 | ||
| Synonymous | -0.213 | 108 | 105 | 1.03 | 0.00000560 | 1006 |
| Loss of Function | 0.755 | 20 | 24.0 | 0.834 | 0.00000101 | 321 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0012 | 0.0012 | notable |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00019 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.00014 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the receptor for type I interferons, including interferons alpha, IFNB1 and IFNW1 (PubMed:2153461, PubMed:7665574, PubMed:10049744, PubMed:14532120, PubMed:15337770, PubMed:21854986). Functions in general as heterodimer with IFNAR2 (PubMed:7665574, PubMed:10049744, PubMed:21854986). Type I interferon binding activates the JAK-STAT signaling cascade, and triggers tyrosine phosphorylation of a number of proteins including JAKs, TYK2, STAT proteins and the IFNR alpha- and beta- subunits themselves (PubMed:7665574, PubMed:21854986). Can form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway (By similarity). {ECO:0000250|UniProtKB:P33896, ECO:0000269|PubMed:10049744, ECO:0000269|PubMed:14532120, ECO:0000269|PubMed:15337770, ECO:0000269|PubMed:19561067, ECO:0000269|PubMed:2153461, ECO:0000269|PubMed:7665574, ECO:0000305|PubMed:21854986}.;
Recessive Scores
- pRec
- 0.0742
Intolerance Scores
- LoFtool
- 0.696
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 57.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.967
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |