QARS1

Chr 3AR

glutaminyl-tRNA synthetase 1

Also known as: GLNRS, MSCCA, PRO2195, QARS

NCBI Gene: 5859 ENSG00000172053 UniProt: P47897 OMIM: 603727

Glutaminyl-tRNA synthetase catalyzes the attachment of glutamine to its cognate tRNA molecules, playing a critical role in brain development. Biallelic mutations cause autosomal recessive microcephaly with progressive seizures and cerebral and cerebellar atrophy. The gene shows minimal constraint against loss-of-function variants (very low pLI), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly, progressive, seizures, and cerebral and cerebellar atrophyMIM #615760

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome · AR · ClinGen 2020

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.64

OE 0.59 (0.43–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.22Z-score

OE missense 0.97 (0.90–1.05)

438 obs / 451.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.43–0.81)

0≤0.351.4

Missense OE?0.97 (0.90–1.05)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 28 / 47.6Missense obs/exp: 438 / 451.2Syn Z: -1.03

Background carrier burden — how many people carry a rare variant somewhere in QARS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

1,118 rare PASS variants

Rare truncating (LoF)

1 in 800

225 rare PASS variants

Rare synonymous (reference)

1 in 120

442 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for QARS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 76	1 in 920
South Asian	~43k	1 in 60	1 in 520
Remaining (unassigned)	~30k	1 in 63	1 in 750
European (Finnish)	~27k	1 in 140	1 in 2,400
Admixed American	~22k	1 in 64	1 in 340
African / African American	~21k	1 in 52	1 in 430
East Asian	~20k	1 in 51	1 in 570
Ashkenazi Jewish	~13k	1 in 410	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 57	1 in 580

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 24 coding exons well covered in gnomAD exomes and genomes.? see exons ↓