YARS1

protein-coding

tyrosyl-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. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. [provided by RefSeq, Jul 2008]

Previous symbols:

YARS

MANE transcript

NM_003680.4

Inheritance

AD, AR

ClinVar variants

P:24U:332B:127

Top phenotype

Neurologic, endocrine, and pancreatic disease, infantile-onset 2

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr1:32,775,237-32,818,031

External References & Databases

Ensembl (ENSG00000134684)

Transcript & Mutation Effects

hg38 • Region Span ~42.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease dominant intermediate CSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012012

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease dominant intermediate CSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012012

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015626

Submitter: ClinGen

YARS1 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2006 (Jordanova et al., PMID: 16429158). At least 8 unique variants have been reported in humans, including missense and indels. Evidence supporting this gene-disease relationship includes case level data, segregation data, and experimental data. Variants in this gene have been reported in at least 8 probands in 6 different publications (PMIDs: 24627108, 27027447, 16429158, 24354524, 26257172, 30373780). Variants in this gene have also segregated with disease in 34 additional family members across two different families. This gene-disease relationship is supported by animal models and functional studies. In drosophila models, expression of mutant YARS1 resulted in progressive motor impairment, electrophysiological deficits, and impaired protein translation (PMIDs: 19561293, 26138142). In cell culture, expression of mutant YARS1 was shown to result in transcriptional dysregulation through alterations of interactions between YARS1 and transcriptional regulators, leading to hyperactivation of E2F1 (PMID:31695036). In summary, YARS1 is DEFINITIVELY associated with autosomal dominant Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease dominant intermediate CSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012012

Submitter: Orphanet

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030375

Submitter: Labcorp Genetics (formerly Invitae)

neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030375

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurologic, endocrine, and pancreatic disease, infantile-onset 2AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Gastrointestinal; Neurologic

Intervention: Audiologic/Otolaryngologic; Endocrine; Gastrointestinal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition may include multiple endocrine abnormalities, including early-onset hypoglycemia, and awareness may allow prompt diagnosis and medical management; Individuals have been described with varying degrees of hepatic dysfunction, and awareness may allow management of sequelae

Refs: 14606043; 16429158; 27633801; 30214071; 30304524; 33490854

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YARS1 variants in ClinVar

25 Conditions Cataloged

Charcot-Marie-Tooth disease dominant intermediate CTotal: 491

not providedTotal: 116

Inborn genetic diseasesTotal: 112

YARS1-related disorderTotal: 62

not specifiedTotal: 51

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2Total: 22

Charcot-Marie-Tooth diseaseTotal: 3

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onsetTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003680.4. 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			4 clinvar	109 clinvar	2 clinvar	115
missense	5 clinvar	14 clinvar	285 clinvar	15 clinvar	1 clinvar	320
nonsense		1 clinvar	11 clinvar			12
start loss						0
frameshift	1 clinvar	2 clinvar	16 clinvar			19
splice donor/acceptor (+/-2bp)		1 clinvar	16 clinvar			17
Total	6	18	332	124	3	483

Highest pathogenic variant AF is 0.000033458906

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003680.4	RefSeq	NP_003671.1	13	MANE Select
ENST00000373477.9	Ensembl	ENSP00000362576.4	13	MANE Select
ENST00000481895.6	Ensembl	ENSP00000502016.1	5	Standard
ENST00000616261.2	Ensembl	ENSP00000484192.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Phenylalanine and Tyrosine Metabolism
Phenylketonuria
Tyrosinemia Type 3 (TYRO3)
Tyrosinemia Type 2 (or Richner-Hanhart syndrome)

Biological Process

tRNA aminoacylation for protein translation
tyrosyl-tRNA aminoacylation
apoptotic process

Molecular Function

tRNA binding
RNA binding
tyrosine-tRNA ligase activity
interleukin-8 receptor binding
protein binding

Cellular Component

extracellular space
cytoplasm
cytosol
nuclear body
aminoacyl-tRNA synthetase multienzyme complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373477
Coding exons: 13
Length: 42915
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.14	228	282	0.809	0.0000158	3449
Missense (PolyPhen)		82	113.76	0.72081		1452
Synonymous	-0.852	124	113	1.10	0.00000674	1037
Loss of Function	3.05	10	27.2	0.368	0.00000137	354

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr- AMP and then transferred to the acceptor end of tRNA(Tyr). {ECO:0000250}.;
Disease: DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type, C (CMTDIC) [MIM:608323]: A 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. The dominant intermediate type C is characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:16429158}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.278

Intolerance Scores

LoFtool: 0.674
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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