GeneBe

IARS1

protein-coding

isoleucyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I|Small nucleolar RNA protein coding host genes|MicroRNA protein coding host genes

Gene summary

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Isoleucine-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family and has been identified as a target of autoantibodies in the autoimmune disease polymyositis/dermatomyositis. Alternatively spliced transcript variants have been found. [provided by RefSeq, Nov 2012]

Previous symbols:
  • IARS

MANE transcript

NM_002161.6

Inheritance

AR

ClinVar variants

P:42U:271B:115

Top phenotype

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr9:92,210,207-92,293,854

External References & Databases

Ensembl (ENSG00000196305)NCBI Gene (3376)OMIM (600709)HGNC:5330GenCCUniProt (P41252)AlphaFoldClinVar (IARS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~83.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

growth retardation, intellectual developmental disorder, hypotonia, and hepatopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014911

Submitter: PanelApp Australia

growth retardation, intellectual developmental disorder, hypotonia, and hepatopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014911

Submitter: Orphanet

growth retardation, intellectual developmental disorder, hypotonia, and hepatopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014911

Submitter: Labcorp Genetics (formerly Invitae)

growth retardation, intellectual developmental disorder, hypotonia, and hepatopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014911

Submitter: G2P

Clinical Genomic Database (CGD)

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathyAR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Patients have been shown to have zinc deficiency (possibly related to chronic liver disease), and medical management (with zinc supplementation) has been shown to be beneficial

Refs: 27426735Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IARS1 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 305
not specifiedTotal: 218
Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathyTotal: 42
IARS1-related disorderTotal: 22
IARS-related disordersTotal: 2
Global developmental delayTotal: 2
MicrocephalyTotal: 2
Inborn genetic diseasesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002161.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
81
clinvar
7
clinvar
 90
missense
6
clinvar
2
clinvar
252
clinvar
20
clinvar
7
clinvar
 287
nonsense
9
clinvar
2
clinvar
2
clinvar
 13
start loss
0
frameshift
7
clinvar
8
clinvar
 15
splice donor/acceptor (+/-2bp)
8
clinvar
15
clinvar
 23
Total222027110114428

Highest pathogenic variant AF is 0.000055762426

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 104 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002161.6RefSeqNP_002152.233MANE Select
ENST00000443024.7EnsemblENSP00000406448.433MANE Select
NM_001374299.1RefSeqNP_001361228.133Standard
NM_001374300.1RefSeqNP_001361229.133Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
iarsDanio rerio

Structure: trunk vasculature

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
  • Amino Acid metabolism
  • tRNA Aminoacylation
  • Translation
  • Metabolism of proteins

Biological Process

  • osteoblast differentiation
  • tRNA aminoacylation for protein translation
  • isoleucyl-tRNA aminoacylation
  • aminoacyl-tRNA metabolism involved in translational fidelity

Molecular Function

  • tRNA binding
  • aminoacyl-tRNA editing activity
  • isoleucine-tRNA ligase activity
  • protein binding
  • ATP binding

Cellular Component

  • cytoplasm
  • cytosol
  • membrane
  • aminoacyl-tRNA synthetase multienzyme complex
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000375643
Coding exons
33
Length
83550
Individuals with no LoFs
125594
Homozygous LoFs
0
Heterozygous LoFs
154
Defined
125748
p
0.000613
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.135946770.8770.00003518281
Missense (PolyPhen)211258.480.81633121
Synonymous-0.8312582421.070.00001262395
Loss of Function3.244676.60.6010.00000410898

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American0.000710.00069rare
Ashkenazi Jewish00.0absent
East Asian0.000880.00087rare
Finnish0.000370.00037rare
European (Non-Finnish)0.000640.00064rare
South Asian0.000690.00069rare
Other0.000980.00098rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. {ECO:0000269|PubMed:8052601}.;

Recessive Scores

pRec
0.192

Intolerance Scores

LoFtool
0.972
RVIS EVS
-1.07
RVIS percentile EVS
7.34

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.997

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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