WARS2

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

Basic information

Region (hg38): 1:119031216-119140654

Links

ENSG00000116874 ∙ NCBI:10352 ∙ OMIM:604733 ∙ HGNC:12730 ∙ Uniprot:Q9UGM6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (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
Parkinsonism-dystonia 3, childhood-onset	AR	Neurologic	The condition may include Parkinsonism features, and response to medical treatment (eg, with levodopa) has been described	Biochemical; Neurologic; Ophthalmologic	28236339; 28650581; 28905505; 29120065; 31970218; 34890876

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WARS2 gene.

• Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (2 variants)
• Inborn genetic diseases (1 variants)
• Parkinsonism-dystonia 3, childhood-onset (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WARS2 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			1	30	4	35
missense	1	7	54	4	3	69
nonsense	1	2	2			5
start loss						0
frameshift	1		4	1		6
inframe indel			2			2
splice donor/acceptor (+/-2bp)			1			1
splice region			1			1
non coding				6	5	11
Total	3	9	64	41	12

Variants in WARS2

This is a list of pathogenic ClinVar variants found in the WARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-119032674-C-G			Benign (May 17, 2021)
1-119032915-A-G			Benign (Jan 23, 2024)
1-119032921-CCCA-C		WARS2-related disorder	Uncertain significance (Jul 29, 2023)
1-119032940-C-T		Inborn genetic diseases	Uncertain significance (Aug 15, 2023)
1-119032958-C-T			Uncertain significance (Feb 08, 2024)
1-119032964-C-A			Uncertain significance (Dec 11, 2019)
1-119032978-G-A		Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures	Uncertain significance (Feb 22, 2019)
1-119032979-A-T			Uncertain significance (Aug 08, 2022)
1-119032981-C-G		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)
1-119032982-CA-C			Uncertain significance (Jan 19, 2022)
1-119032984-A-G			Uncertain significance (Aug 02, 2022)
1-119033006-G-A		Inborn genetic diseases	Uncertain significance (Mar 22, 2021)
1-119033031-A-T			Likely benign (Apr 25, 2023)
1-119033038-C-T			Uncertain significance (Dec 18, 2023)
1-119033045-T-C			Uncertain significance (Jul 19, 2022)
1-119033056-T-A		Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures • Inborn genetic diseases • WARS2-related disorder	Conflicting classifications of pathogenicity (Nov 17, 2023)
1-119033064-C-T		WARS2-related disorder	Benign (Jan 29, 2024)
1-119033069-C-A		Inborn genetic diseases	Uncertain significance (Dec 26, 2023)
1-119033095-G-A		Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures	Uncertain significance (Nov 01, 2022)
1-119033107-C-A			Uncertain significance (Jul 12, 2022)
1-119033109-C-T			Likely benign (Jul 14, 2023)
1-119033110-G-A			Uncertain significance (Jan 22, 2024)
1-119033112-G-A			Likely benign (Aug 04, 2023)
1-119033112-G-T		Parkinsonism-dystonia 3, childhood-onset	Uncertain significance (Dec 21, 2022)
1-119033117-G-A		Inborn genetic diseases	Uncertain significance (May 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WARS2	protein_coding	protein_coding	ENST00000235521	6	109456

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0509	0.945	125713	0	35	125748	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.902	174	211	0.825	0.0000125	2324
Missense in Polyphen		58	85.851	0.67559		967
Synonymous	0.691	79	87.2	0.906	0.00000559	733
Loss of Function	2.52	5	15.8	0.317	8.44e-7	180

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000122	0.000122
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.000601	0.000601
European (Non-Finnish)	0.000142	0.000141
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mitochondrial aminoacyl-tRNA synthetase that activate and transfer the amino acids to their corresponding tRNAs during the translation of mitochondrial genes and protein synthesis. {ECO:0000305|PubMed:28650581}.
• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Tryptophan Metabolism;tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Tryptophan metabolism;Tryptophan degradation;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.278

Intolerance Scores

• loftool: 0.356
• rvis_EVS: 0.24
• rvis_percentile_EVS: 69.37

Haploinsufficiency Scores

• pHI: 0.139
• hipred: Y
• hipred_score: 0.580
• ghis: 0.490

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.570

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wars2
• Phenotype: hearing/vestibular/ear 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); muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: wars2
• Affected structure: trabecular layer
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: vasculogenesis;tRNA aminoacylation for protein translation;tryptophanyl-tRNA aminoacylation;mitochondrial tryptophanyl-tRNA aminoacylation
• Cellular component: mitochondrion;mitochondrial matrix;plasma membrane
• Molecular function: tryptophan-tRNA ligase activity;ATP binding