HARS1

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

Basic information

Region (hg38): 5:140673035-140691537

Previous symbols: [ "USH3B", "HARS" ]

Links

ENSG00000170445

∙ NCBI:3035 ∙ OMIM:142810 ∙ HGNC:4816 ∙ Uniprot:P12081 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

Usher syndrome type 3B (Limited), mode of inheritance: AR
Usher syndrome type 3 (Supportive), mode of inheritance: AR
autosomal dominant Charcot-Marie-Tooth disease type 2W (Supportive), mode of inheritance: AD
autosomal dominant Charcot-Marie-Tooth disease type 2W (Strong), mode of inheritance: AD
Usher syndrome type 3B (Strong), mode of inheritance: AR
Usher syndrome type 3 (Refuted Evidence), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Usher syndrome, type IIIB	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Neurologic; Ophthalmologic	22279524; 22930593; 26072516
Hearing loss data unclear but suggestive of early loss

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HARS1 gene.

Usher_syndrome_type_3B (540 variants)
not_provided (130 variants)
not_specified (111 variants)
Autosomal_dominant_Charcot-Marie-Tooth_disease_type_2W (16 variants)
HARS1-related_disorder (10 variants)
Spastic_ataxia (5 variants)
Intellectual_disability (4 variants)
Dysarthria (4 variants)
Peripheral_neuropathy (3 variants)
Retinal_dystrophy (3 variants)
Urinary_urgency (2 variants)
Dysmetria (2 variants)
Distal_muscle_weakness (2 variants)
Motor_delay (2 variants)
Inborn_genetic_diseases (2 variants)
Microcephaly (2 variants)
Scoliosis (2 variants)
Oculomotor_apraxia (2 variants)
Pes_planus (2 variants)
Tremor (2 variants)
Cerebellar_ataxia (2 variants)
Choreoathetosis (2 variants)
Nystagmus (2 variants)
Hammertoe (2 variants)
Joint_laxity (2 variants)
Cerebellar_atrophy (2 variants)
HARS1-related_multi-system_ataxia_syndrome (1 variants)
Pes_cavus (1 variants)
Retinitis_pigmentosa-deafness_syndrome (1 variants)
Usher_syndrome_type_3 (1 variants)
Charcot-Marie-Tooth_disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HARS1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002109.6. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	105 clinvar	1 clinvar	112
missense	4 clinvar	5 clinvar	285 clinvar	28 clinvar	4 clinvar	326
nonsense		2 clinvar	13 clinvar			15
start loss			2			2
frameshift	1 clinvar	1 clinvar	14 clinvar			16
splice donor/acceptor (+/-2bp)		1 clinvar	7 clinvar			8
Total	5	9	327	133	5

Highest pathogenic variant AF is 0.0000731063

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HARS1	protein_coding	protein_coding	ENST00000504156	13	18852

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000238	0.996	125699	0	49	125748	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.26	239	301	0.795	0.0000177	3288
Missense in Polyphen		72	109.47	0.6577		1169
Synonymous	1.23	97	114	0.853	0.00000594	1022
Loss of Function	2.54	14	28.7	0.488	0.00000153	328

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000268	0.000268
Ashkenazi Jewish	0.00	0.00
East Asian	0.000217	0.000217
Finnish	0.0000927	0.0000924
European (Non-Finnish)	0.000317	0.000308
Middle Eastern	0.000217	0.000217
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Cytoplasmic histidine--tRNA ligase (Probable). Plays a role in axon guidance. {ECO:0000269|PubMed:26072516, ECO:0000305}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 2W (CMT2W) [MIM:616625]: An autosomal dominant, 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. CMT2W patients manifest a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment. Most patients also have upper limb involvement. {ECO:0000269|PubMed:22930593, ECO:0000269|PubMed:26072516}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Aminoacyl-tRNA biosynthesis - Homo sapiens (human);Histidine Metabolism;Histidinemia;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;Allograft Rejection;tRNA Aminoacylation;Translation;Metabolism of proteins;tRNA charging;Cytosolic tRNA aminoacylation;Histidine degradation (Consensus)

Intolerance Scores

loftool: 0.554
rvis_EVS: 0.26
rvis_percentile_EVS: 70.52

Haploinsufficiency Scores

pHI: 0.248
hipred: Y
hipred_score: 0.591
ghis: 0.533

Essentials

essential_gene_CRISPR: E
essential_gene_CRISPR2: E
essential_gene_gene_trap: E
gene_indispensability_pred: E
gene_indispensability_score: 0.996

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Hars
Phenotype: hearing/vestibular/ear phenotype;

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;mitochondrial translation
Cellular component: cytoplasm;mitochondrion;cytosol
Molecular function: histidine-tRNA ligase activity;ATP binding;identical protein binding