GeneBe

YARS2

protein-coding

tyrosyl-tRNA synthetase 2, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

MANE transcript

NM_001040436.3

Inheritance

AR

ClinVar variants

P:40U:145B:113

Top phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 2

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr12:32,727,490-32,755,897

External References & Databases

Ensembl (ENSG00000139131)NCBI Gene (51067)OMIM (610957)HGNC:24249GenCCUniProt (Q9Y2Z4)AlphaFoldClinVar (YARS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~28.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *YARS2* and *YARS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 29, 2024. The *YARS2* gene encodes mitochondrial tyrosyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits. The *YARS2* gene was first reported in relation to autosomal recessive *YARS2*-related primary mitochondrial disease in 2010 (PMID: 20598274). YARS2 has been associated with a single disease entity to date; myopathy, lactic acidosis, and sideroblastic anemia 2 [OMIM#613561]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *YARS2*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants (six missense, one in-frame duplication, one nonsense) identified in seven unrelated cases from five publications (PMIDs: 20598274, 24344687, 22504945, 25638461, 28395030). Onset is typically in childhood and clinical features in affected individuals are variable and include sideroblastic anemia, lethargy, exercise intolerance, muscle weakness, respiratory insufficiency, dysphagia, hypertrophic cardiomyopathy, failure to thrive, and lactic acidemia. Muscle biopsies have shown ragged red fibers, decreased COX staining, and variable respiratory chain complex enzyme deficiencies. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), rescue in patient cells (PMID: 22504945), and rescue in a cell culture model (PMID: 33610547). In summary, there is definitive evidence to support the relationship between *YARS2* and autosomal recessive *YARS2*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 29, 2024 (SOP Version 10).

myopathy, lactic acidosis, and sideroblastic anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000863

Submitter: Orphanet

myopathy, lactic acidosis, and sideroblastic anemia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013307

Submitter: Labcorp Genetics (formerly Invitae)

myopathy, lactic acidosis, and sideroblastic anemia 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013307

Submitter: Ambry Genetics

myopathy, lactic acidosis, and sideroblastic anemia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013307

Submitter: PanelApp Australia

myopathy, lactic acidosis, and sideroblastic anemia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013307

Submitter: G2P

Clinical Genomic Database (CGD)

Myopathy, lactic acidosis, and sideroblastic anemia 2AR

Manifestation: Cardiovascular; Hematologic; Musculoskeletal

Intervention: Cardiovascular; Hematologic

Rationale: Individuals may develop transfusion-dependent sideroblastic anemia in infancy; Surveillance for cardiovascular manifestations may allow early medical interventions

Refs: 20598274; 22504945; 24344687; 24430573Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YARS2 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 276
Inborn genetic diseasesTotal: 70
Myopathy, lactic acidosis, and sideroblastic anemia 2Total: 44
not specifiedTotal: 22
YARS2-related disorderTotal: 19
Mitochondrial diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040436.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
104
clinvar
1
clinvar
 106
missense
3
clinvar
11
clinvar
138
clinvar
7
clinvar
 159
nonsense
6
clinvar
2
clinvar
2
clinvar
 10
start loss
0
frameshift
12
clinvar
5
clinvar
1
clinvar
 18
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
1
clinvar
 5
Total21191451121298

Highest pathogenic variant AF is 0.00017408069

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001040436.3RefSeqNP_001035526.15MANE Select
ENST00000324868.13EnsemblENSP00000320658.85MANE Select
ENST00000548490.1EnsemblENSP00000447710.13Standard
ENST00000874022.1EnsemblENSP00000544081.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
  • tRNA Aminoacylation
  • Translation
  • Metabolism of proteins
  • Tyrosine metabolism

Biological Process

  • translation
  • tRNA aminoacylation for protein translation
  • tRNA aminoacylation
  • mitochondrial tyrosyl-tRNA aminoacylation

Molecular Function

  • tRNA binding
  • RNA binding
  • tyrosine-tRNA ligase activity
  • protein binding
  • ATP binding

Cellular Component

  • mitochondrion
  • mitochondrial matrix
  • cytosol
  • nuclear body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000324868
Coding exons
5
Length
28413
Individuals with no LoFs
125327
Homozygous LoFs
1
Heterozygous LoFs
420
Defined
125748
p
0.00168
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2642472590.9540.00001303074
Missense (PolyPhen)6272.1490.85934874
Synonymous-0.9661211081.120.000005521013
Loss of Function0.6291821.10.8520.00000126205

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0120.012notable
Latino/Admixed American0.00200.0020notable
Ashkenazi Jewish00.0absent
East Asian0.000330.00033rare
Finnish0.00300.0030notable
European (Non-Finnish)0.000620.00062rare
South Asian0.000260.00026rare
Other0.000490.00049rare

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:0000269|PubMed:15779907, ECO:0000269|PubMed:17997975}.;
Disease
DISEASE: Myopathy with lactic acidosis and sideroblastic anemia 2 (MLASA2) [MIM:613561]: A rare oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Affected individuals manifest sideroblastic anemia, progressive lethargy, muscle weakness, and exercise intolerance associated with persistent lactic acidemia. {ECO:0000269|PubMed:20598274, ECO:0000269|PubMed:22504945}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.285

Intolerance Scores

LoFtool
0.846
RVIS EVS
-0.47
RVIS percentile EVS
23.43

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.992

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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