rs767667312
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005051.3(QARS1):c.1567C>T(p.Arg523Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000929 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
QARS1
NM_005051.3 stop_gained
NM_005051.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 4.60
Genes affected
QARS1 (HGNC:9751): (glutaminyl-tRNA synthetase 1) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-49099391-G-A is Pathogenic according to our data. Variant chr3-49099391-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 566178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
QARS1 | NM_005051.3 | c.1567C>T | p.Arg523Ter | stop_gained | 17/24 | ENST00000306125.12 | |
QARS1 | NM_001272073.2 | c.1534C>T | p.Arg512Ter | stop_gained | 17/24 | ||
QARS1 | XM_017006965.3 | c.1567C>T | p.Arg523Ter | stop_gained | 17/23 | ||
QARS1 | NR_073590.2 | n.1542C>T | non_coding_transcript_exon_variant | 17/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
QARS1 | ENST00000306125.12 | c.1567C>T | p.Arg523Ter | stop_gained | 17/24 | 1 | NM_005051.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251464Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727242
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 17, 2022 | _x000D_This variant was identified as compound heterozygous with NM_005051.3:c.1132C>T. Criteria applied: PVS1, PM3, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 22, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 566178). This variant has not been reported in the literature in individuals affected with QARS-related conditions. This variant is present in population databases (rs767667312, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg523*) in the QARS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in QARS are known to be pathogenic (PMID: 24656866, 25471517). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
0.37, 0.37, 0.39
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at