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rs58012546

chr3-49104426-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005051.3(QARS1):c.163C>T(p.Leu55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,224 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 28 hom. )

Consequence

QARS1
NM_005051.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.53
Variant links:
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 Benign. Variant got -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-49104426-G-A is Benign according to our data. Variant chr3-49104426-G-A is described in ClinVar as [Benign]. Clinvar id is 381869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=3.53 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00216 (329/152360) while in subpopulation EAS AF= 0.0162 (84/5186). AF 95% confidence interval is 0.0134. There are 2 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
QARS1NM_005051.3 linkuse as main transcriptc.163C>T p.Leu55= synonymous_variant 2/24 ENST00000306125.12
QARS1NM_001272073.2 linkuse as main transcriptc.163C>T p.Leu55= synonymous_variant 2/24
QARS1XM_017006965.3 linkuse as main transcriptc.163C>T p.Leu55= synonymous_variant 2/23
QARS1NR_073590.2 linkuse as main transcriptn.187C>T non_coding_transcript_exon_variant 2/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
QARS1ENST00000306125.12 linkuse as main transcriptc.163C>T p.Leu55= synonymous_variant 2/241 NM_005051.3 P1P47897-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00215
AC:
327
AN:
152242
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000651
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0109
Gnomad ASJ
AF:
0.00662
Gnomad EAS
AF:
0.0164
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00366
AC:
921
AN:
251440
Hom.:
12
AF XY:
0.00294
AC XY:
400
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000984
Gnomad AMR exome
AF:
0.0167
Gnomad ASJ exome
AF:
0.00486
Gnomad EAS exome
AF:
0.0116
Gnomad SAS exome
AF:
0.000523
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000290
Gnomad OTH exome
AF:
0.00293
GnomAD4 exome
AF:
0.00144
AC:
2107
AN:
1461864
Hom.:
28
Cov.:
32
AF XY:
0.00135
AC XY:
983
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0169
Gnomad4 ASJ exome
AF:
0.00490
Gnomad4 EAS exome
AF:
0.0228
Gnomad4 SAS exome
AF:
0.000452
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000175
Gnomad4 OTH exome
AF:
0.00108
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00216
AC:
329
AN:
152360
Hom.:
2
Cov.:
32
AF XY:
0.00231
AC XY:
172
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.000649
Gnomad4 AMR
AF:
0.0110
Gnomad4 ASJ
AF:
0.00662
Gnomad4 EAS
AF:
0.0162
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000830
Hom.:
1
Bravo
AF:
0.00267
Asia WGS
AF:
0.00635
AC:
22
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000356

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 29, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 09, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
QARS1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 07, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2022QARS1: BS1, BS2 -
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 08, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
Cadd
Benign
9.9
Dann
Benign
0.81
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs58012546; hg19: chr3-49141859; COSMIC: COSV60275037; COSMIC: COSV60275037; API