IARS2

isoleucyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class I

Basic information

Region (hg38): 1:220094132-220148041

Links

ENSG00000067704 ∙ NCBI:55699 ∙ OMIM:612801 ∙ HGNC:29685 ∙ Uniprot:Q9NSE4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Limited), mode of inheritance: AR
• cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Supportive), mode of inheritance: AR
• cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Strong), mode of inheritance: AR
• cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome (Limited), mode of inheritance: Unknown
• Leigh syndrome (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia	AR	Audiologic/Otolaryngologic; Endocrine	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Awareness of growth hormone deficiency may allow early recognition and treatment	Audiologic/Otolaryngologic; Craniofacial; Endocrine; Musculoskeletal; Ophthalmologic; Neurologic	8409271; 25130867

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IARS2 gene.

• not provided (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IARS2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				89	6	95
missense		2	167	8	4	181
nonsense	3	3	2			8
start loss						0
frameshift	4	2	1			7
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1	1		3
splice region			13	21	10	44
non coding			4	84	32	120
Total	7	8	175	182	42

Highest pathogenic variant AF is 0.000119

Variants in IARS2

This is a list of pathogenic ClinVar variants found in the IARS2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-220094182-G-T		not specified	Likely benign (Nov 15, 2017)
1-220094217-A-C			Pathogenic (Jul 08, 2024)
1-220094222-T-C			Likely benign (Aug 19, 2023)
1-220094232-C-T		Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
1-220094234-C-T			Likely benign (Dec 07, 2023)
1-220094239-G-T		not specified	Benign (Jan 31, 2024)
1-220094241-G-A			Uncertain significance (Oct 14, 2022)
1-220094246-G-A			Likely benign (May 08, 2023)
1-220094248-G-T			Uncertain significance (Mar 14, 2022)
1-220094249-C-T			Likely benign (Nov 03, 2022)
1-220094257-C-T		not specified • IARS2-related disorder	Benign (Jan 28, 2024)
1-220094271-C-G		Inborn genetic diseases	Uncertain significance (Nov 26, 2021)
1-220094271-C-T			Likely pathogenic (Aug 05, 2018)
1-220094284-G-A		Inborn genetic diseases	Uncertain significance (Jun 06, 2023)
1-220094290-C-T			Uncertain significance (May 23, 2022)
1-220094294-C-T			Likely benign (Jan 02, 2024)
1-220094295-C-T		Inborn genetic diseases	Uncertain significance (Jan 06, 2023)
1-220094301-T-C			Uncertain significance (Oct 18, 2022)
1-220094309-G-C			Likely benign (Jul 24, 2021)
1-220094317-A-G			Uncertain significance (Nov 27, 2023)
1-220094327-G-C		not specified • IARS2-related disorder	Benign (Jul 01, 2024)
1-220094353-C-T		IARS2-related disorder	Likely benign (Jan 19, 2024)
1-220094358-G-C			Uncertain significance (Sep 01, 2022)
1-220094369-C-G		Inborn genetic diseases	Likely benign (Feb 27, 2023)
1-220094373-C-T		Inborn genetic diseases	Uncertain significance (Mar 18, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IARS2	protein_coding	protein_coding	ENST00000302637	23	53937

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0813	0.919	125679	0	69	125748	0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.17	479	557	0.860	0.0000290	6588
Missense in Polyphen		127	203.2	0.62499		2422
Synonymous	0.678	190	202	0.939	0.0000112	1933
Loss of Function	5.26	14	56.8	0.246	0.00000284	695

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000356	0.000352
Ashkenazi Jewish	0.000601	0.000595
East Asian	0.000273	0.000272
Finnish	0.000140	0.000139
European (Non-Finnish)	0.000311	0.000308
Middle Eastern	0.000273	0.000272
South Asian	0.000349	0.000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia (CAGSSS) [MIM:616007]: An autosomal recessive disorder characterized by cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, skeletal dysplasia, scoliosis, and facial dysmorphism. {ECO:0000269|PubMed:25130867}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Valine, leucine and isoleucine degradation;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.126

Intolerance Scores

• loftool: 0.789
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.68

Haploinsufficiency Scores

• pHI: 0.497
• hipred: N
• hipred_score: 0.372
• ghis: 0.598

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Iars2

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;isoleucyl-tRNA aminoacylation;mitochondrial translation;aminoacyl-tRNA metabolism involved in translational fidelity
• Cellular component: mitochondrion;mitochondrial matrix;cytosol
• Molecular function: tRNA binding;aminoacyl-tRNA editing activity;isoleucine-tRNA ligase activity;ATP binding