GeneBe

QARS1

protein-coding

glutaminyl-tRNA synthetase 1, the group of MicroRNA protein coding host genes|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. In metazoans, 9 aminoacyl-tRNA synthetases specific for glutamine (gln), glutamic acid (glu), and 7 other amino acids are associated within a multienzyme complex. Although present in eukaryotes, glutaminyl-tRNA synthetase (QARS) is absent from many prokaryotes, mitochondria, and chloroplasts, in which Gln-tRNA(Gln) is formed by transamidation of the misacylated Glu-tRNA(Gln). Glutaminyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

Previous symbols:
  • QARS

MANE transcript

NM_005051.3

Inheritance

AR

ClinVar variants

P:87U:431B:237

Top phenotype

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr3:49,095,932-49,105,130

External References & Databases

Ensembl (ENSG00000172053)NCBI Gene (5859)OMIM (603727)HGNC:9751GenCCUniProt (P47897)AlphaFoldClinVar (QARS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~9.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014335

Submitter: PanelApp Australia

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014335

Submitter: Orphanet

microcephaly-short stature-intellectual disability-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018494

Submitter: Orphanet

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014335

Submitter: ClinGen

QARS was reported in relation to diffuse cerebral and cerebellar atrophy-intractable seizures – progressive microcephaly syndrome in 2014 (PMID: 24656866). Evidence supporting this gene-disease relationship is case-level data and functional characterization. Variants in this gene have been reported in at least 8 individuals, including 2 sets of affected siblings (PMID: 27717089, 31618474, 25471517, 25432320, 24656866). This is insufficient to reach the maximum amount of case level data. However, several additional pathogenic LoF variants are reported in ClinVar. Variants in this gene are known to disrupt the protein interactions with other disease genes, RARS (PMID: 24656866). Additionally a knock-out zebrafish model was generated with recapitulated the human phenotype (PMID: 24656866). The mechanism for disease is loss of function. In summary, QARS is definitively associated with diffuse cerebral and cerebellar atrophy-intractable seizures – progressive microcephaly syndrome.

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014335

Submitter: G2P

Clinical Genomic Database (CGD)

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophyAR

Manifestation: Craniofacial; 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: 24656866Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to QARS1 variants in ClinVar

10 Conditions Cataloged
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndromeTotal: 920
not providedTotal: 213
Inborn genetic diseasesTotal: 127
not specifiedTotal: 100
QARS1-related disorderTotal: 24
QARS-related disordersTotal: 4
MicrocephalyTotal: 2
See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005051.3. 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
7
clinvar
218
clinvar
3
clinvar
 228
missense
15
clinvar
408
clinvar
15
clinvar
1
clinvar
 439
nonsense
13
clinvar
6
clinvar
2
clinvar
 21
start loss
2
clinvar
 2
frameshift
25
clinvar
6
clinvar
2
clinvar
 33
splice donor/acceptor (+/-2bp)
20
clinvar
12
clinvar
 32
Total40474312334755

Highest pathogenic variant AF is 0.00008054483

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005051.3RefSeqNP_005042.124MANE Select
ENST00000306125.12EnsemblENSP00000307567.624MANE Select
NM_001272073.2RefSeqNP_001259002.124Standard
ENST00000414533.5EnsemblENSP00000390015.124Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
qarsDanio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
  • 2-Hydroxyglutric Aciduria (D And L Form)
  • Homocarnosinosis
  • Hyperinsulinism-Hyperammonemia Syndrome
  • Succinic semialdehyde dehydrogenase deficiency

Biological Process

  • tRNA aminoacylation for protein translation
  • glutaminyl-tRNA aminoacylation
  • negative regulation of protein kinase activity
  • brain development
  • negative regulation of stress-activated MAPK cascade

Molecular Function

  • glutamine-tRNA ligase activity
  • protein kinase inhibitor activity
  • protein binding
  • ATP binding
  • protein kinase binding

Cellular Component

  • cytoplasm
  • mitochondrial matrix
  • cytosol
  • aminoacyl-tRNA synthetase multienzyme complex
  • protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000306125
Coding exons
24
Length
9189
Individuals with no LoFs
125656
Homozygous LoFs
0
Heterozygous LoFs
92
Defined
125748
p
0.000366
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2204384510.9710.00002675022
Missense (PolyPhen)203232.080.874692638
Synonymous-1.031841671.100.000008841529
Loss of Function2.642847.60.5880.00000257533

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000430.00043rare
Latino/Admixed American0.000580.00058rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.000450.00045rare
South Asian0.000360.00036rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Glutamine--tRNA ligase (PubMed:26869582). Plays a critical role in brain development (PubMed:24656866). {ECO:0000269|PubMed:24656866, ECO:0000269|PubMed:26869582}.;

Recessive Scores

pRec
0.189

Intolerance Scores

LoFtool
0.889
RVIS EVS
-0.64
RVIS percentile EVS
16.68

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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