FARS2

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

Basic information

Region (hg38): 6:5261043-5829192

Previous symbols: [ "FARS1" ]

Links

ENSG00000145982 ∙ NCBI:10667 ∙ OMIM:611592 ∙ HGNC:21062 ∙ Uniprot:O95363 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined oxidative phosphorylation defect type 14 (Moderate), mode of inheritance: AR
• hereditary spastic paraplegia 77 (Limited), mode of inheritance: AR
• combined oxidative phosphorylation defect type 14 (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 77 (Supportive), mode of inheritance: AR
• combined oxidative phosphorylation defect type 14 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 77 (Strong), mode of inheritance: AR
• Leigh syndrome (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Combined oxidative phosphorylation deficiency 14; Spastic paraplegia 77, autosomal recessive	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	Biochemical; Musculoskeletal; Neurologic	22499341; 22833457; 26553276

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FARS2 gene.

• Combined oxidative phosphorylation defect type 14 (378 variants)
• not provided (91 variants)
• Inborn genetic diseases (27 variants)
• not specified (19 variants)
• Hereditary spastic paraplegia 77 (12 variants)
• FARS2-related condition (3 variants)
• See cases (3 variants)
• Combined oxidative phosphorylation defect type 14;Hereditary spastic paraplegia 77 (2 variants)
• FARS2-Related Disorders (1 variants)
• Hereditary spastic paraplegia 77;Combined oxidative phosphorylation defect type 14 (1 variants)
• Global developmental delay;Mitochondrial encephalomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FARS2 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			2	93	5	100
missense	1	18	174	4	3	200
nonsense	12					12
start loss		1				1
frameshift	5	3				8
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1	2				3
splice region			7	9		16
non coding			5	37	28	70
Total	19	24	183	134	36

Highest pathogenic variant AF is 0.0000460

Variants in FARS2

This is a list of pathogenic ClinVar variants found in the FARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-5261059-G-A			Benign (Jun 14, 2018)
6-5261075-T-G			Benign (Jul 14, 2018)
6-5261126-A-G			Benign (Jun 14, 2018)
6-5261155-C-T			Likely benign (Oct 05, 2018)
6-5261227-A-C			Benign (Jun 14, 2018)
6-5261233-GAGGCCGCGTTGCCCGGGTTACCGA-G			Benign (Jul 08, 2018)
6-5261307-C-T			Benign (Dec 21, 2021)
6-5261342-T-C			Benign (Jun 29, 2018)
6-5261368-T-C			Benign (Jun 29, 2018)
6-5261370-T-C			Benign (Jun 29, 2018)
6-5261375-T-C			Benign (Jun 29, 2018)
6-5261420-G-C			Likely benign (Apr 13, 2020)
6-5261448-A-G			Benign (Jun 29, 2018)
6-5261612-A-G			Benign (Jun 29, 2018)
6-5261754-A-T			Benign (Jun 29, 2018)
6-5368278-C-T			Likely benign (Aug 14, 2018)
6-5368573-G-T		Combined oxidative phosphorylation defect type 14	Pathogenic (Jul 14, 2023)
6-5368574-G-T		Combined oxidative phosphorylation defect type 14	Uncertain significance (Sep 27, 2022)
6-5368576-G-A		Combined oxidative phosphorylation defect type 14	Likely benign (Apr 13, 2023)
6-5368577-G-A		Combined oxidative phosphorylation defect type 14	Uncertain significance (May 22, 2023)
6-5368578-G-T		Intellectual disability	Likely benign (Jan 01, 2019)
6-5368581-C-G		Combined oxidative phosphorylation defect type 14	Pathogenic (Jun 22, 2023)
6-5368587-T-C		Combined oxidative phosphorylation defect type 14	Uncertain significance (Mar 03, 2022)
6-5368590-G-A		Combined oxidative phosphorylation defect type 14	Uncertain significance (Nov 27, 2021)
6-5368591-G-T		Combined oxidative phosphorylation defect type 14	Conflicting classifications of pathogenicity (Dec 21, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FARS2	protein_coding	protein_coding	ENST00000324331	6	510537

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.30e-9	0.509	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.682	232	263	0.882	0.0000151	2979
Missense in Polyphen		81	102.95	0.78678		1117
Synonymous	-0.503	110	103	1.06	0.00000617	860
Loss of Function	1.04	15	20.0	0.748	0.00000103	216

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000326	0.000326
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000229	0.000229
Middle Eastern	0.000164	0.000163
South Asian	0.0000686	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. To a lesser extent, also catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins. {ECO:0000269|PubMed:19549855, ECO:0000269|PubMed:22833457}.
• Disease: DISEASE: Combined oxidative phosphorylation deficiency 14 (COXPD14) [MIM:614946]: A severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. {ECO:0000269|PubMed:22499341, ECO:0000269|PubMed:22833457}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 77, autosomal recessive (SPG77) [MIM:617046]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:26553276}. 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;Tyrosine metabolism;tRNA charging;Mitochondrial tRNA aminoacylation (Consensus)

Recessive Scores

• pRec: 0.139

Intolerance Scores

• loftool: 0.734
• rvis_EVS: -0.07
• rvis_percentile_EVS: 48.69

Haploinsufficiency Scores

• pHI: 0.0829
• hipred: N
• hipred_score: 0.231
• ghis: 0.537

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fars2

Gene ontology

• Biological process: tRNA aminoacylation for protein translation;phenylalanyl-tRNA aminoacylation;tRNA processing
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix
• Molecular function: tRNA binding;phenylalanine-tRNA ligase activity;protein binding;ATP binding