rs141983717
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_005051.3(QARS1):c.316G>A(p.Asp106Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00023 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 1 hom. )
Consequence
QARS1
NM_005051.3 missense
NM_005051.3 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 3.77
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 Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.035427123).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000387 (59/152314) while in subpopulation AMR AF= 0.00137 (21/15300). AF 95% confidence interval is 0.000919. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
QARS1 | NM_005051.3 | c.316G>A | p.Asp106Asn | missense_variant | 3/24 | ENST00000306125.12 | NP_005042.1 | |
QARS1 | NM_001272073.2 | c.283G>A | p.Asp95Asn | missense_variant | 3/24 | NP_001259002.1 | ||
QARS1 | XM_017006965.3 | c.316G>A | p.Asp106Asn | missense_variant | 3/23 | XP_016862454.2 | ||
QARS1 | NR_073590.2 | n.291G>A | non_coding_transcript_exon_variant | 3/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
QARS1 | ENST00000306125.12 | c.316G>A | p.Asp106Asn | missense_variant | 3/24 | 1 | NM_005051.3 | ENSP00000307567.6 |
Frequencies
GnomAD3 genomes AF: 0.000394 AC: 60AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000275 AC: 69AN: 251280Hom.: 0 AF XY: 0.000324 AC XY: 44AN XY: 135854
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GnomAD4 exome AF: 0.000214 AC: 313AN: 1461764Hom.: 1 Cov.: 31 AF XY: 0.000232 AC XY: 169AN XY: 727164
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GnomAD4 genome AF: 0.000387 AC: 59AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2024 | Observed in heterozygous state in an individual with neuronal seroid lipofuscinosis, epilepsy, and vermis hypoplasia, who also harbored a heterozygous variant in CNTNAP2 (PMID: 33528079); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25888430, 34406647, 25471517, 33528079, Hussein2023[Preprint]) - |
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 106 of the QARS protein (p.Asp106Asn). This variant is present in population databases (rs141983717, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 409237). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 13, 2021 | - - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 20, 2021 | ACMG categories: PM2 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;.;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N;.;.;.;.
REVEL
Benign
Sift
Benign
T;T;.;T;.;.;.;.
Sift4G
Benign
T;T;T;T;.;.;.;.
Polyphen
P;.;.;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at