HARS2

protein-coding

histidyl-tRNA synthetase 2, mitochondrial, 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 an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

Previous symbols:

HARSL

MANE transcript

NM_012208.4

Inheritance

ClinVar variants

P:38U:144B:54

Top phenotype

Perrault syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr5:140,691,430-140,699,305

External References & Databases

Ensembl (ENSG00000112855)

Transcript & Mutation Effects

hg38 • Region Span ~7.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Perrault syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013972

Submitter: Labcorp Genetics (formerly Invitae)

Perrault syndrome 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013972

Submitter: ClinGen

The relationship between HARS2 and autosomal recessive Perrault syndrome was evaluated using the ClinGen Clinical Validity Framework as of 11/20/2017. Variants in HARS2 were first reported in humans with this disease as early as 2011 (Pierce et al.). At least 3 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 3 probands in 2 publications (21464306, 27650058). Variants in this gene segregated with disease in 4 additional family members. Experimental evidence from S. cerevisiae and C. elegans models provide some evidence of the gene-disease association. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 5/15/2018.

Perrault syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013972

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Perrault syndrome 2AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Genitourinary; Obstetric

Intervention: Audiologic/Otolaryngologic

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

Comments: Females have been described as being affected by genitourinary anomalies in addition to hearing impairment

Refs: 517579; 21464306

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HARS2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 204

Inborn genetic diseasesTotal: 70

Perrault syndrome 2Total: 33

not specifiedTotal: 28

HARS2-related disorderTotal: 25

HARS2-related disordersTotal: 6

Perrault syndromeTotal: 4

Sensorineural hearing loss disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012208.4. 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			2 clinvar	43 clinvar	1 clinvar	46
missense	4 clinvar	13 clinvar	136 clinvar	10 clinvar		163
nonsense	1 clinvar	5 clinvar	2 clinvar			8
start loss						0
frameshift	4 clinvar	4 clinvar	4 clinvar			12
splice donor/acceptor (+/-2bp)		7 clinvar				7
Total	9	29	144	53	1	236

Highest pathogenic variant AF is 0.00014937326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012208.4	RefSeq	NP_036340.1	13	MANE Select
ENST00000230771.9	Ensembl	ENSP00000230771.3	13	MANE Select
NM_001278731.2	RefSeq	NP_001265660.1	12	Standard
NM_001278732.2	RefSeq	NP_001265661.1	9	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
tRNA Aminoacylation
Translation

Biological Process

translation
tRNA aminoacylation for protein translation
histidyl-tRNA aminoacylation

Molecular Function

RNA binding
histidine-tRNA ligase activity
protein binding
ATP binding
identical protein binding

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000230771
Coding exons: 13
Length: 7879
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 87
Defined: 125748
p: 0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0439	265	267	0.992	0.0000152	3296
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0015	0.0015	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00042	0.00042	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.633
RVIS EVS: -0.4
RVIS percentile EVS: 26.53

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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