HARS1

protein-coding

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

Gene summary

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Previous symbols:

USH3B
HARS

MANE transcript

NM_002109.6

Inheritance

AR, AD

ClinVar variants

P:15U:375B:146

Top phenotype

Usher syndrome, type IIIB

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr5:140,673,035-140,691,537

External References & Databases

Ensembl (ENSG00000170445)

Transcript & Mutation Effects

hg38 • Region Span ~18.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Usher syndrome type 3BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013788

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016485

Submitter: Orphanet

Usher syndrome type 3BLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013788

Submitter: G2P

autosomal dominant Charcot-Marie-Tooth disease type 2WSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014711

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant Charcot-Marie-Tooth disease type 2WSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014711

Submitter: Orphanet

Usher syndrome type 3NO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0016485

Submitter: ClinGen

There is no convincing evidence supporting the association between HARS and autosomal recessive Usher syndrome type 3.

Usher syndrome type 3BLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013788

Submitter: PanelApp Australia

autosomal dominant Charcot-Marie-Tooth disease type 2WSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014711

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Usher syndrome, type IIIBAR

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Hearing loss data unclear but suggestive of early loss

Refs: 22279524; 22930593; 26072516

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HARS1 variants in ClinVar

34 Conditions Cataloged

Usher syndrome type 3BTotal: 576

not providedTotal: 182

not specifiedTotal: 164

HARS1-related disorderTotal: 39

Autosomal dominant Charcot-Marie-Tooth disease type 2WTotal: 16

Spastic ataxiaTotal: 5

Intellectual disabilityTotal: 4

DysarthriaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002109.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	116 clinvar		123
missense	4 clinvar	6 clinvar	323 clinvar	27 clinvar	3 clinvar	363
nonsense		1 clinvar	17 clinvar			18
start loss			2 clinvar			2
frameshift	1 clinvar	2 clinvar	15 clinvar			18
splice donor/acceptor (+/-2bp)		1 clinvar	11 clinvar			12
Total	5	10	375	143	3	536

Highest pathogenic variant AF is 0.0000731063

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002109.6	RefSeq	NP_002100.2	13	MANE Select
ENST00000504156.7	Ensembl	ENSP00000425634.1	13	MANE Select
NM_001258040.3	RefSeq	NP_001244969.1	12	Standard
NM_001258041.3	RefSeq	NP_001244970.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hars	Danio rerio	Structure: cranial blood vessel Quality: increased branchiness abnormal

Gene / Model

Organism

Observed Phenotype

hars

Danio rerio

Structure: cranial blood vessel

Quality: increased branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Histidine Metabolism
Histidinemia
miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase

Biological Process

translation
tRNA aminoacylation for protein translation
histidyl-tRNA aminoacylation
mitochondrial translation

Molecular Function

histidine-tRNA ligase activity
ATP binding
identical protein binding

Cellular Component

cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000504156
Coding exons: 13
Length: 18852
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	239	301	0.795	0.0000177	3288
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00032	0.00031	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Intolerance Scores

LoFtool: 0.554
RVIS EVS: 0.26
RVIS percentile EVS: 70.52

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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