WARS1

protein-coding

tryptophanyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. Tryptophanyl-tRNA synthetase (WARS) catalyzes the aminoacylation of tRNA(trp) with tryptophan and is induced by interferon. Tryptophanyl-tRNA synthetase belongs to the class I tRNA synthetase family. Four transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

IFI53
WARS

MANE transcript

NM_004184.4

Inheritance

AD, AR

ClinVar variants

P:9U:97B:27

Top phenotype

Neuronopathy, distal hereditary motor, type IX

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr14:100,333,790-100,376,805

External References & Databases

Ensembl (ENSG00000140105)

Transcript & Mutation Effects

hg38 • Region Span ~43.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

distal hereditary motor neuropathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018894

Submitter: G2P

neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957218

Submitter: G2P

distal hereditary motor neuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018894

Submitter: ClinGen

WARS1 encodes the tryptophanyl-tRNA synthetase 1 that catalyzes the aminoacylation of tRNA(trp) with tryptophan, the first step of protein synthesis and an essential step in the cell's protein synthesis machinery. WARS1 functions in the same aminoacylation pathway as other known neuropathy genes, such GARS1, YARS1, and HARS1. In 2017, three families, two Taiwanese and one Belgian, were shown to carry the same heterozygous His257Arg missense variant in WARS1 co-segregating with a juvenile onset distal motor neuropathy phenotype (PMID: 28369220). The authors show evidence of a dominant-negative effect of the His257Arg mutation capable of dimerizing with the wild-type protein and impairing the overall aminoacylation function. When transfected into neuronal-like cells, an effect on neurite length was also observed. Two other WARS1 missense variants have been linked with this consistent juvenile onset HMN phenotype since then (PMID: 31321409). In these two families, significant segregation or de novo inheritance was shown, but functional evidence was absent. The phenotype in all five published WARS1 families is very consistent, a juvenile onset motor neuropathy phenotype affecting both upper and lower limbs without any sensory involvement. The panel concludes that the evidence for the pathogenicity of the His257Arg mutation is sufficient to link WARS1 to the motor neuropathy phenotype. More reports will solidify the gene-disease relationship in the future. Based on the curated evidence, we classify the gene-disease relationship of WARS1 and autosomal dominant motor neuropathy as limited, but with the advice to include it on panels. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.

neuronopathy, distal hereditary motor, type 9MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060585

Submitter: Broad Center for Mendelian Genomics

neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957218

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, type 9MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060585

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, type 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060585

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neuronopathy, distal hereditary motor, type IXAD

Manifestation: Neurologic

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: 28369220; 31069783; 31321409

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WARS1 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 65

not providedTotal: 41

not specifiedTotal: 20

WARS1-related disorderTotal: 14

Neuronopathy, distal hereditary motor, type 9Total: 10

Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalitiesTotal: 9

See casesTotal: 2

WARS-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004184.4. 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				17 clinvar		17
missense		6 clinvar	90 clinvar	9 clinvar	1 clinvar	106
nonsense		2 clinvar	1 clinvar			3
start loss	1 clinvar					1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	8	97	26	1	133

Highest pathogenic variant AF is 0.00024239643

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 157 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004184.4	RefSeq	NP_004175.2	10	MANE Select
ENST00000392882.7	Ensembl	ENSP00000376620.2	10	MANE Select
NM_173701.2	RefSeq	NP_776049.1	10	Standard
NM_213645.2	RefSeq	NP_998810.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Tryptophan Metabolism
Photodynamic therapy-induced unfolded protein response
Amino Acid metabolism
Tryptophan metabolism

Biological Process

angiogenesis
negative regulation of protein phosphorylation
translation
tRNA aminoacylation for protein translation
tryptophanyl-tRNA aminoacylation

Molecular Function

tryptophan-tRNA ligase activity
protein binding
ATP binding
kinase inhibitor activity
protein kinase binding

Cellular Component

nucleus
cytoplasm
cytosol
protein-containing complex
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355338
Coding exons: 10
Length: 43018
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125746
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.99	188	282	0.666	0.0000161	3170
Missense (PolyPhen)		27	101.91	0.26493		1197
Synonymous	1.01	101	115	0.880	0.00000767	868
Loss of Function	3.28	5	21.4	0.234	0.00000107	251

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1, isoform 2 and T1-TrpRS have aminoacylation activity while T2-TrpRS lacks it. Isoform 2, T1-TrpRS and T2-TrpRS possess angiostatic activity whereas isoform 1 lacks it. T2-TrpRS inhibits fluid shear stress-activated responses of endothelial cells. Regulates ERK, Akt, and eNOS activation pathways that are associated with angiogenesis, cytoskeletal reorganization and shear stress-responsive gene expression. {ECO:0000269|PubMed:11773625, ECO:0000269|PubMed:11773626, ECO:0000269|PubMed:1373391, ECO:0000269|PubMed:14630953, ECO:0000269|PubMed:28369220}.;
Disease: DISEASE: Neuronopathy, distal hereditary motor, 9 (HMN9) [MIM:617721]: An autosomal dominant neurologic disorder characterized by juvenile onset of slowly progressive distal muscle weakness and atrophy affecting both the lower and upper limbs. {ECO:0000269|PubMed:28369220}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.420

Intolerance Scores

LoFtool: 0.425
RVIS EVS: -0.27
RVIS percentile EVS: 34.6

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.933

Gene Damage Prediction

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