rs748978904
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005051.3(QARS1):āc.1972G>Cā(p.Val658Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
QARS1
NM_005051.3 missense
NM_005051.3 missense
Scores
1
5
11
Clinical Significance
Conservation
PhyloP100: 4.63
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.32756895).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
QARS1 | NM_005051.3 | c.1972G>C | p.Val658Leu | missense_variant | 21/24 | ENST00000306125.12 | |
QARS1 | NM_001272073.2 | c.1939G>C | p.Val647Leu | missense_variant | 21/24 | ||
QARS1 | XM_017006965.3 | c.1972G>C | p.Val658Leu | missense_variant | 21/23 | ||
QARS1 | NR_073590.2 | n.1947G>C | non_coding_transcript_exon_variant | 21/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
QARS1 | ENST00000306125.12 | c.1972G>C | p.Val658Leu | missense_variant | 21/24 | 1 | NM_005051.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251162Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135812
GnomAD3 exomes
AF:
AC:
1
AN:
251162
Hom.:
AF XY:
AC XY:
0
AN XY:
135812
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 exome
AF:
AC:
3
AN:
1461858
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727236
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74374
GnomAD4 genome
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74374
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2022 | The c.1972G>C (p.V658L) alteration is located in exon 21 (coding exon 21) of the QARS gene. This alteration results from a G to C substitution at nucleotide position 1972, causing the valine (V) at amino acid position 658 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with QARS-related disease. This variant is present in population databases (rs748978904, ExAC 0.01%). This sequence change replaces valine with leucine at codon 658 of the QARS protein (p.Val658Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.
REVEL
Benign
Sift
Benign
T;D;D;.
Sift4G
Benign
T;T;T;T
Polyphen
0.93
.;P;.;.
Vest4
0.75, 0.74, 0.76
MutPred
0.74
.;Loss of glycosylation at S655 (P = 0.0839);.;.;
MVP
MPC
0.84
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at