IRAG1
protein-codinginositol 1,4,5-triphosphate receptor associated 1
Gene summary
This gene is similar to a putative mouse tumor suppressor gene (Mrvi1) that is frequently disrupted by mouse AIDS-related virus (MRV). The encoded protein, which is found in the membrane of the endoplasmic reticulum, is similar to Jaw1, a lymphoid-restricted protein whose expression is down-regulated during lymphoid differentiation. This protein is a substrate of cGMP-dependent kinase-1 (PKG1) that can function as a regulator of IP3-induced calcium release. Studies in mouse suggest that MRV integration at Mrvi1 induces myeloid leukemia by altering the expression of a gene important for myeloid cell growth and/or differentiation, and thus this gene may function as a myeloid leukemia tumor suppressor gene. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene, and alternative translation start sites, including a non-AUG (CUG) start site, are used. [provided by RefSeq, May 2011]
- MRVI1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~120.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008698
Submitter: LiferaOmics
Genetic evidence – Published: PMID: 32573102 – Reports isolated familial achalasia in a Tunisian family with three affected individuals, all homozygous for a truncating variant; both parents are heterozygous carriers and four unaffected siblings are heterozygous. Case-level (biallelic predicted null in AR model; homozygous scored once for a single proband) = 1.5; segregation (two additional affected siblings counted as segregation + parental carrier confirmation; conservative) = 1.5; case-control = 0; PMID: 32573102 total = 3.0 Published genetic evidence total = 3.0/12 Genetic evidence – Our cases: Family 1 one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity not stated) = 1.5; segregation = 0; case-control = 0; Family 1 total = 1.5 Our cases total = 1.5/12 Total genetic evidence (published + our cases) 3.0 + 1.5 = 4.5/12 Experimental evidence – Published: PMID: 32573102 – Functional alteration in engineered cells showing truncated IRAG mislocalization and loss of interaction with cGK1β, supporting a LoF mechanism relevant to achalasia (NO–cGMP smooth muscle relaxation pathway). Functional alteration = 1.0; PMID: 32573102 experimental total = 1.0 PMID: 20080989 - IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation. Expression and protein Interaction = 1.0 Experimental evidence total = 2.0/6 Overall score = 4.5 + 2.0 = 6.5 Overall score = 6.5
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IRAG1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_130385.4. 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 | 2 | 7 | |||
| missense | 162 | 12 | 3 | 177 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 170 | 14 | 3 | 187 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_569056.4 | 21 | MANE Select | |
| Ensembl | ENSP00000412130.2 | 21 | MANE Select | |
| RefSeq | NP_001092049.2 | 20 | Standard | |
| RefSeq | NP_001093633.1 | 19 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vascular smooth muscle contraction - Homo sapiens (human)
- cGMP-PKG signaling pathway - Homo sapiens (human)
- Hemostasis
- cGMP effects
- Nitric oxide stimulates guanylate cyclase
Molecular Function
- protein binding
Cellular Component
- endoplasmic reticulum membrane
- integral component of membrane
- sarcoplasmic reticulum
- platelet dense tubular network membrane
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000423302
- Coding exons
- 21
- Length
- 120898
- Individuals with no LoFs
- 125444
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 47
- Defined
- 125491
- p
- 0.000187
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.451 | 477 | 506 | 0.944 | 0.0000290 | 5833 |
| Missense (PolyPhen) | 182 | 197.16 | 0.92309 | 2284 | ||
| Synonymous | 1.34 | 179 | 203 | 0.880 | 0.0000121 | 1851 |
| Loss of Function | 3.53 | 19 | 44.4 | 0.428 | 0.00000220 | 551 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00052 | 0.00050 | rare |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000058 | 0.000054 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00016 | 0.00015 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00034 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role as NO/PRKG1-dependent regulator of IP3- induced calcium release; its phosphorylation by PRKG1 inhibits bradykinin and IP3-induced calcium release from intracellular stores. Recruits PRKG1 to the endoplasmic reticulum and may mediate the assembly of PRKG1 and ITPR1 in a macrocomplex. Involved in PRKG1 signaling cascade leading to inhibition of platelet activation and aggregation. Mediates also NO-dependent inhibition of calcium signaling in gastrointestinal smooth muscle contributing to NO-dependent relaxation. {ECO:0000269|PubMed:14729908}.;
Recessive Scores
- pRec
- 0.110
Intolerance Scores
- RVIS EVS
- 2.07
- RVIS percentile EVS
- 97.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.479
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |