AARS2

alanyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class II

Basic information

Region (hg38): 6:44298731-44313347

Previous symbols: [ "AARSL" ]

Links

ENSG00000124608 ∙ NCBI:57505 ∙ OMIM:612035 ∙ HGNC:21022 ∙ Uniprot:Q5JTZ9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined oxidative phosphorylation defect type 8 (Moderate), mode of inheritance: AR
• leukoencephalopathy, progressive, with ovarian failure (Moderate), mode of inheritance: AR
• leukoencephalopathy, progressive, with ovarian failure (Definitive), mode of inheritance: AR
• ovarioleukodystrophy (Supportive), mode of inheritance: AR
• hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia (Supportive), mode of inheritance: AD
• combined oxidative phosphorylation defect type 8 (Supportive), mode of inheritance: AR
• leukoencephalopathy, progressive, with ovarian failure (Strong), mode of inheritance: AR
• combined oxidative phosphorylation defect type 8 (Strong), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leukoencephalopathy, progressive, with ovarian failure	AR	Obstetric	Females may suffer from premature ovarian failure, and measures to allow reproduction (eg,through egg preservation) may be desired	Biochemical; Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Obstetric	21549344; 24808023; 25058219

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AARS2 gene.

• not provided (13 variants)
• Combined oxidative phosphorylation defect type 8 (8 variants)
• Leukoencephalopathy, progressive, with ovarian failure (4 variants)
• Pulmonary hypoplasia (1 variants)
• AARS2-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AARS2 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			9	70	6	85
missense	3	11	177	14	6	211
nonsense	8	6	1			15
start loss		1				1
frameshift	7	5				12
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	4	4	2			10
splice region		1	5	16	2	24
non coding			37	63	50	150
Total	22	28	228	147	62

Highest pathogenic variant AF is 0.0000854

Variants in AARS2

This is a list of pathogenic ClinVar variants found in the AARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-44298736-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44298827-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44298828-A-G		Combined oxidative phosphorylation defect type 8	Benign (Jan 13, 2018)
6-44298837-C-A		Combined oxidative phosphorylation defect type 8	Benign (Jan 12, 2018)
6-44298841-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44298911-C-CTT		Combined oxidative phosphorylation deficiency	Benign (Jun 14, 2016)
6-44298944-G-C		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44298971-T-C		Combined oxidative phosphorylation defect type 8	Benign (Jan 13, 2018)
6-44298998-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44299011-C-G		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44299062-C-T		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44299073-AC-A		Combined oxidative phosphorylation deficiency	Uncertain significance (Jun 14, 2016)
6-44299074-C-A		Combined oxidative phosphorylation defect type 8	Benign (Jan 13, 2018)
6-44299076-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44299188-T-C		Combined oxidative phosphorylation defect type 8	Benign (Jan 12, 2018)
6-44299221-T-C		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44299237-A-G		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44299247-G-A		Combined oxidative phosphorylation defect type 8	Benign (Jan 13, 2018)
6-44299254-T-C		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44299259-CTTCT-C		Combined oxidative phosphorylation deficiency	Uncertain significance (Jun 14, 2016)
6-44299262-CT-C		Combined oxidative phosphorylation deficiency	Benign (Jun 14, 2016)
6-44299295-T-G		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)
6-44299350-G-A		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 12, 2018)
6-44299434-C-CT		Combined oxidative phosphorylation deficiency	Uncertain significance (Jun 14, 2016)
6-44299502-C-T		Combined oxidative phosphorylation defect type 8	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AARS2	protein_coding	protein_coding	ENST00000244571	22	13673

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.98e-17	0.976	125628	0	120	125748	0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0725	567	572	0.991	0.0000363	6235
Missense in Polyphen		192	214.6	0.89468		2413
Synonymous	1.88	198	235	0.844	0.0000134	2157
Loss of Function	2.56	35	55.6	0.630	0.00000345	547

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000972	0.000951
Ashkenazi Jewish	0.000103	0.0000992
East Asian	0.000550	0.000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000671	0.000668
Middle Eastern	0.000550	0.000544
South Asian	0.000232	0.000229
Other	0.000163	0.000163

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). Also edits incorrectly charged tRNA(Ala) via its editing domain. {ECO:0000255|HAMAP-Rule:MF_03133}.
• Disease: DISEASE: Combined oxidative phosphorylation deficiency 8 (COXPD8) [MIM:614096]: A mitochondrial disease characterized by a lethal infantile hypertrophic cardiomyopathy, generalized muscle dysfunction and some neurologic involvement. The liver is not affected. {ECO:0000269|PubMed:21549344}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukoencephalopathy, progressive, with ovarian failure (LKENP) [MIM:615889]: An autosomal recessive neurodegenerative disorder characterized by childhood- to adulthood-onset of signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. Brain MRI shows leukoencephalopathy with striking involvement of deep white matter, and cerebellar atrophy. All female patients develop premature ovarian failure. {ECO:0000269|PubMed:24808023}. 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;Translation;Metabolism of proteins;tRNA charging;Mitochondrial tRNA aminoacylation;Glycine, serine, alanine and threonine metabolism (Consensus)

Recessive Scores

• pRec: 0.112

Intolerance Scores

• loftool: 0.814
• rvis_EVS: 1.14
• rvis_percentile_EVS: 92.37

Haploinsufficiency Scores

• pHI: 0.143
• hipred: N
• hipred_score: 0.426
• ghis: 0.491

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.992

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Aars2
• Phenotype: 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); 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)

Gene ontology

• Biological process: tRNA modification;alanyl-tRNA aminoacylation;mitochondrial respiratory chain complex assembly;mitochondrial alanyl-tRNA aminoacylation
• Cellular component: mitochondrion
• Molecular function: tRNA binding;alanine-tRNA ligase activity;ATP binding;zinc ion binding;amino acid binding