HARS2

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

Basic information

Region (hg38): 5:140691430-140699305

Previous symbols: [ "HARSL" ]

Links

ENSG00000112855 ∙ NCBI:23438 ∙ OMIM:600783 ∙ HGNC:4817 ∙ Uniprot:P49590 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Perrault syndrome 2 (Strong), mode of inheritance: AR
• Perrault syndrome (Supportive), mode of inheritance: AR
• Perrault syndrome 2 (Limited), mode of inheritance: AR
• Perrault syndrome 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Perrault syndrome 2	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Endocrine; Genitourinary; Obstetric	517579; 21464306
Females have been described as being affected by genitourinary anomalies in addition to hearing impairment

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HARS2 gene.

• not provided (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HARS2 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	34	1	36
missense		5	73	5		83
nonsense	1	1	2			4
start loss						0
frameshift	2		2			4
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			4	7		11
non coding	1		3	31	10	45
Total	4	6	83	70	11

Highest pathogenic variant AF is 0.0000263

Variants in HARS2

This is a list of pathogenic ClinVar variants found in the HARS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-140691617-C-T		not specified	Likely benign (Nov 10, 2016)
5-140691645-C-G		not specified	Uncertain significance (Jun 08, 2015)
5-140691647-C-T		not specified	Uncertain significance (May 09, 2017)
5-140691655-C-G		not specified	Conflicting classifications of pathogenicity (Aug 01, 2024)
5-140691667-C-T		Inborn genetic diseases	Uncertain significance (Apr 23, 2024)
5-140691714-GC-G			Pathogenic (Oct 05, 2023)
5-140691720-C-A		Sensorineural hearing loss disorder	Likely pathogenic (Jan 17, 2019)
5-140691721-G-C			Uncertain significance (Jul 24, 2023)
5-140691721-GCTTCGTGCACCGGGGCGGTCCGTTGCC-G			Uncertain significance (Sep 15, 2022)
5-140691724-T-G		Inborn genetic diseases	Uncertain significance (Sep 26, 2022)
5-140691726-G-A			Likely benign (Feb 05, 2022)
5-140691742-C-G			Uncertain significance (Jul 23, 2022)
5-140691743-G-T			Uncertain significance (Jan 08, 2024)
5-140691748-C-A		Inborn genetic diseases	Uncertain significance (May 05, 2023)
5-140693295-G-T			Likely benign (Jul 17, 2018)
5-140693331-CA-C			Benign (Aug 06, 2019)
5-140693331-C-CA			Likely benign (Aug 10, 2019)
5-140693478-TC-T		HARS2-related disorder	Likely benign (Oct 28, 2020)
5-140693499-G-A		HARS2-related disorder	Likely benign (Aug 16, 2019)
5-140693596-A-G		HARS2-related disorder	Likely benign (Dec 11, 2020)
5-140693606-T-C			Likely benign (Oct 03, 2023)
5-140693607-T-G			Conflicting classifications of pathogenicity (Mar 01, 2024)
5-140693619-T-A		Perrault syndrome 2	Likely pathogenic (May 20, 2019)
5-140693627-C-T		not specified	Uncertain significance (Jul 17, 2023)
5-140693633-G-A			Uncertain significance (Sep 11, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HARS2	protein_coding	protein_coding	ENST00000230771	13	7879

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000279	0.997	125661	0	87	125748	0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0439	265	267	0.992	0.0000152	3296
Missense in Polyphen		74	82.817	0.89354		943
Synonymous	-0.390	103	98.1	1.05	0.00000455	1000
Loss of Function	2.60	12	26.4	0.454	0.00000142	327

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000337	0.000337
Ashkenazi Jewish	0.00	0.00
East Asian	0.00147	0.00147
Finnish	0.00	0.00
European (Non-Finnish)	0.000352	0.000352
Middle Eastern	0.00147	0.00147
South Asian	0.000425	0.000425
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Histidine Metabolism;Histidinemia;tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Histidine metabolism;Mitochondrial tRNA aminoacylation;Histidine degradation (Consensus)

Recessive Scores

• pRec: 0.146

Intolerance Scores

• loftool: 0.633
• rvis_EVS: -0.4
• rvis_percentile_EVS: 26.53

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.283
• ghis: 0.599

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• 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: Hars2

Zebrafish Information Network

• Gene name: hars
• Affected structure: cranial blood vessel
• Phenotype tag: abnormal
• Phenotype quality: increased branchiness

Gene ontology

• Biological process: translation;tRNA aminoacylation for protein translation;histidyl-tRNA aminoacylation
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix;cytosol
• Molecular function: RNA binding;histidine-tRNA ligase activity;protein binding;ATP binding;identical protein binding;protein homodimerization activity