EPRS1

protein-coding

glutamyl-prolyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I|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 multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. Alternative splicing has been observed for this gene, but the full-length nature and biological validity of the variant have not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

QPRS
QARS
EPRS

MANE transcript

NM_004446.3

Inheritance

ClinVar variants

P:25U:298B:134

Top phenotype

Leukodystrophy, hypomyelinating, 15

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr1:219,968,600-220,046,530

External References & Databases

Ensembl (ENSG00000136628)

Transcript & Mutation Effects

hg38 • Region Span ~77.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy, hypomyelinating, 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054782

Submitter: G2P

leukodystrophy, hypomyelinating, 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054782

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054782

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating, 15AR

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: General

Rationale: 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

Refs: 29576217

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPRS1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 354

Inborn genetic diseasesTotal: 183

not specifiedTotal: 52

Leukodystrophy, hypomyelinating, 15Total: 36

EPRS1-related disorderTotal: 34

EPRS-related disordersTotal: 3

Global developmental delayTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004446.3. 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			4 clinvar	100 clinvar	2 clinvar	106
missense	4 clinvar	2 clinvar	285 clinvar	26 clinvar	6 clinvar	323
nonsense	7 clinvar	4 clinvar	1 clinvar			12
start loss						0
frameshift	3 clinvar	3 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)		2 clinvar	7 clinvar			9
Total	14	11	298	126	8	457

Highest pathogenic variant AF is 0.000008055352

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004446.3	RefSeq	NP_004437.2	32	MANE Select
ENST00000366923.8	Ensembl	ENSP00000355890.3	32	MANE Select
ENST00000477030.2	Ensembl	ENSP00000477493.1	6	Standard
ENST00000609181.5	Ensembl	ENSP00000477245.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Hyperornithinemia with gyrate atrophy (HOGA)
Creatine deficiency, guanidinoacetate methyltransferase deficiency
L-arginine:glycine amidinotransferase deficiency

Biological Process

tRNA aminoacylation for protein translation
glutamyl-tRNA aminoacylation
prolyl-tRNA aminoacylation
negative regulation of translation
cellular response to insulin stimulus

Molecular Function

glutamate-tRNA ligase activity
proline-tRNA ligase activity
protein binding
ATP binding
zinc ion binding

Cellular Component

cytoplasm
cytosol
plasma membrane
membrane
aminoacyl-tRNA synthetase multienzyme complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366923
Coding exons: 32
Length: 78058
Individuals with no LoFs: 125664
Homozygous LoFs: 0
Heterozygous LoFs: 84
Defined: 125748
p: 0.000334

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.60	669	796	0.841	0.0000402	9951
Missense (PolyPhen)		207	293.17	0.70607		3441
Synonymous	-1.54	301	269	1.12	0.0000136	2785
Loss of Function	5.28	31	82.9	0.374	0.00000420	1037

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00050	0.00049	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0.00057	0.00052	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Multifunctional protein which is primarily part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex, that catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA (PubMed:1756734, PubMed:24100331, PubMed:23263184). The phosphorylation of EPRS, induced by interferon-gamma, dissociates the protein from the aminoacyl-tRNA synthetase multienzyme complex and recruits it to the GAIT complex that binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin), suppressing their translation. Interferon-gamma can therefore redirect, in specific cells, the EPRS function from protein synthesis to translation inhibition (PubMed:15479637, PubMed:23071094). Also functions as an effector of the mTORC1 signaling pathway by promoting, through SLC27A1, the uptake of long-chain fatty acid by adipocytes. Thereby, it also plays a role in fat metabolism and more indirectly influences lifespan (PubMed:28178239). {ECO:0000269|PubMed:15479637, ECO:0000269|PubMed:1756734, ECO:0000269|PubMed:23071094, ECO:0000269|PubMed:23263184, ECO:0000269|PubMed:24100331, ECO:0000269|PubMed:28178239}.;
Disease: DISEASE: Leukodystrophy, hypomyelinating, 15 (HLD15) [MIM:617951]: An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with thinning of the corpus callosum. Clinical features include motor and cognitive impairment appearing in the first or second decade of life, dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. {ECO:0000269|PubMed:29576217}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.529

Intolerance Scores

LoFtool: 0.778
RVIS EVS: -0.12
RVIS percentile EVS: 44.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.985

Gene Damage Prediction

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