AARS1

alanyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class II

Basic information

Region (hg38): 16:70251982-70289707

Previous symbols: [ "AARS" ]

Links

ENSG00000090861 ∙ NCBI:16 ∙ OMIM:601065 ∙ HGNC:20 ∙ Uniprot:P49588 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease axonal type 2N (Supportive), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease axonal type 2N (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy, 29 (Strong), mode of inheritance: AR
• undetermined early-onset epileptic encephalopathy (Definitive), mode of inheritance: AR
• trichothiodystrophy 8, nonphotosensitive (Limited), mode of inheritance: AR
• trichothiodystrophy 8, nonphotosensitive (Limited), mode of inheritance: Unknown
• Charcot-Marie-Tooth disease axonal type 2N (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2N; Developmental and epileptic encephalopathy 29	AD/AR	General	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	Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Neurologic	6492094; 20045102; 22206013; 22009580; 22573628; 25817015; 33909043
Charcot-Marie-Tooth disease, axonal, type 2N can include hearing loss, which is described as postlingual; For epileptic encephalopathy, as with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AARS1 gene.

• Charcot-Marie-Tooth disease type 2 (998 variants)
• not provided (257 variants)
• Inborn genetic diseases (179 variants)
• Charcot-Marie-Tooth disease axonal type 2N (101 variants)
• not specified (56 variants)
• Charcot-Marie-Tooth disease (29 variants)
• Developmental and epileptic encephalopathy, 29 (25 variants)
• AARS1-related condition (5 variants)
• Charcot-Marie-Tooth disease axonal type 2N;Developmental and epileptic encephalopathy, 29;Leukoencephalopathy, hereditary diffuse, with spheroids 2;Trichothiodystrophy 8, nonphotosensitive (3 variants)
• Trichothiodystrophy 8, nonphotosensitive (3 variants)
• Charcot-Marie-Tooth disease axonal type 2N;Leukoencephalopathy, hereditary diffuse, with spheroids 2;Trichothiodystrophy 8, nonphotosensitive;Developmental and epileptic encephalopathy, 29 (2 variants)
• See cases (2 variants)
• Leukoencephalopathy, hereditary diffuse, with spheroids 2;Trichothiodystrophy 8, nonphotosensitive;Charcot-Marie-Tooth disease axonal type 2N;Developmental and epileptic encephalopathy, 29 (2 variants)
• Charcot-Marie-Tooth disease axonal type 2N;Developmental and epileptic encephalopathy, 29 (2 variants)
• Developmental and epileptic encephalopathy, 29;Charcot-Marie-Tooth disease axonal type 2N (2 variants)
• Peripheral neuropathy (1 variants)
• Charcot-Marie-Tooth disease axonal type 2N;Developmental and epileptic encephalopathy, 29;Trichothiodystrophy 8, nonphotosensitive;Leukoencephalopathy, hereditary diffuse, with spheroids 2 (1 variants)
• 8 conditions (1 variants)
• Distal spinal muscular atrophy (1 variants)
• AARS-related disorders (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AARS1 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			8	230	4	242
missense	5	6	521	14	2	548
nonsense	7		13			20
start loss						0
frameshift	6	2	11			19
inframe indel			4			4
splice donor/acceptor (+/-2bp)		3	6			9
splice region			29	45	1	75
non coding			11	160	35	206
Total	18	11	574	404	41

Highest pathogenic variant AF is 0.0000131

Variants in AARS1

This is a list of pathogenic ClinVar variants found in the AARS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-70252397-C-T		Charcot-Marie-Tooth disease axonal type 2N	Uncertain significance (Jan 13, 2018)
16-70252470-T-G		Charcot-Marie-Tooth disease axonal type 2N	Benign/Likely benign (Dec 23, 2018)
16-70252508-G-A		Charcot-Marie-Tooth disease axonal type 2N	Likely benign (Jan 13, 2018)
16-70252552-G-C		Charcot-Marie-Tooth disease axonal type 2N	Uncertain significance (Jan 13, 2018)
16-70252580-T-C		Charcot-Marie-Tooth disease axonal type 2N	Benign (Jan 13, 2018)
16-70252590-C-T		Charcot-Marie-Tooth disease axonal type 2N	Uncertain significance (Jan 12, 2018)
16-70252647-T-A		Charcot-Marie-Tooth disease axonal type 2N	Benign (Jun 16, 2018)
16-70252689-A-G		Charcot-Marie-Tooth disease axonal type 2N	Uncertain significance (Jan 12, 2018)
16-70252722-C-G		Charcot-Marie-Tooth disease type 2	Uncertain significance (Aug 14, 2023)
16-70252727-C-G		Charcot-Marie-Tooth disease type 2 • Inborn genetic diseases	Uncertain significance (Sep 07, 2022)
16-70252728-T-A		Charcot-Marie-Tooth disease type 2 • Charcot-Marie-Tooth disease axonal type 2N • not specified • Leukoencephalopathy, hereditary diffuse, with spheroids 2;Trichothiodystrophy 8, nonphotosensitive;Charcot-Marie-Tooth disease axonal type 2N;Developmental and epileptic encephalopathy, 29	Benign/Likely benign (Apr 01, 2024)
16-70252738-C-T		Charcot-Marie-Tooth disease type 2	Uncertain significance (Oct 17, 2023)
16-70252739-G-A		Charcot-Marie-Tooth disease type 2	Likely benign (Aug 31, 2022)
16-70252739-G-C		Charcot-Marie-Tooth disease type 2	Likely benign (Jul 18, 2022)
16-70252746-A-G		Charcot-Marie-Tooth disease type 2	Uncertain significance (Jan 25, 2024)
16-70252748-C-G		Inborn genetic diseases • Charcot-Marie-Tooth disease type 2	Uncertain significance (Sep 03, 2023)
16-70252749-T-G		Charcot-Marie-Tooth disease type 2	Uncertain significance (Jun 05, 2019)
16-70252755-A-G		Developmental and epileptic encephalopathy, 29	Likely pathogenic (Apr 25, 2018)
16-70252756-AG-A			Uncertain significance (Feb 08, 2018)
16-70252758-G-C		Charcot-Marie-Tooth disease type 2 • Inborn genetic diseases	Uncertain significance (Apr 20, 2023)
16-70252758-G-T		Charcot-Marie-Tooth disease type 2	Uncertain significance (Sep 27, 2023)
16-70252760-A-C		Charcot-Marie-Tooth disease type 2	Likely benign (Aug 14, 2023)
16-70252761-G-A		Charcot-Marie-Tooth disease type 2	Uncertain significance (Jul 19, 2022)
16-70252761-G-C		Charcot-Marie-Tooth disease type 2	Uncertain significance (Apr 19, 2023)
16-70252765-C-G		Charcot-Marie-Tooth disease type 2	Uncertain significance (Jun 28, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AARS1	protein_coding	protein_coding	ENST00000261772	20	37249

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.82e-8	1.00	125665	0	83	125748	0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0519	538	541	0.994	0.0000333	6347
Missense in Polyphen		218	238.81	0.91284		2706
Synonymous	-0.956	231	213	1.08	0.0000136	1921
Loss of Function	3.75	22	50.9	0.432	0.00000335	541

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000907	0.000907
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000276	0.000273
Middle Eastern	0.000326	0.000326
South Asian	0.000359	0.000359
Other	0.000652	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala- AMP and then transferred to the acceptor end of tRNA(Ala) (PubMed:27622773, PubMed:27911835, PubMed:28493438). Also edits incorrectly charged tRNA(Ala) via its editing domain (PubMed:27622773, PubMed:27911835, PubMed:28493438). {ECO:0000255|HAMAP-Rule:MF_03133, ECO:0000269|PubMed:27622773, ECO:0000269|PubMed:27911835, ECO:0000269|PubMed:28493438}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 2N (CMT2N) [MIM:613287]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:20045102, ECO:0000269|PubMed:22009580, ECO:0000269|PubMed:22206013}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 29 (EIEE29) [MIM:616339]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE29 patients manifest severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination. {ECO:0000269|PubMed:25817015, ECO:0000269|PubMed:28493438}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Pyruvate Carboxylase Deficiency;Primary Hyperoxaluria Type I;Lactic Acidemia;Alanine Metabolism;tRNA Aminoacylation;Alanine Aspartate Asparagine metabolism;Translation;Metabolism of proteins;tRNA charging;Cytosolic tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.205

Intolerance Scores

• loftool: 0.643
• rvis_EVS: -0.66
• rvis_percentile_EVS: 16.12

Haploinsufficiency Scores

• pHI: 0.398
• hipred: Y
• hipred_score: 0.558
• ghis: 0.538

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.958

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Aars
• Phenotype: cellular phenotype; muscle phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: tRNA modification;tRNA aminoacylation for protein translation;alanyl-tRNA aminoacylation;tRNA processing;cerebellar Purkinje cell layer development;negative regulation of neuron apoptotic process;neuromuscular process controlling balance;aminoacyl-tRNA metabolism involved in translational fidelity;regulation of cytoplasmic translational fidelity
• Cellular component: cytoplasm;cytosol;membrane;extracellular exosome
• Molecular function: tRNA binding;aminoacyl-tRNA editing activity;Ser-tRNA(Ala) hydrolase activity;alanine-tRNA ligase activity;ATP binding;zinc ion binding;amino acid binding;translation regulator activity