rs141983717

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

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.77
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 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
QARS1NM_005051.3 linkuse as main transcriptc.316G>A p.Asp106Asn missense_variant 3/24 ENST00000306125.12 NP_005042.1 P47897-1B7Z840
QARS1NM_001272073.2 linkuse as main transcriptc.283G>A p.Asp95Asn missense_variant 3/24 NP_001259002.1 P47897-2B7Z840
QARS1XM_017006965.3 linkuse as main transcriptc.316G>A p.Asp106Asn missense_variant 3/23 XP_016862454.2
QARS1NR_073590.2 linkuse as main transcriptn.291G>A non_coding_transcript_exon_variant 3/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
QARS1ENST00000306125.12 linkuse as main transcriptc.316G>A p.Asp106Asn missense_variant 3/241 NM_005051.3 ENSP00000307567.6 P47897-1

Frequencies

GnomAD3 genomes
AF:
0.000394
AC:
60
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00137
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000275
AC:
69
AN:
251280
Hom.:
0
AF XY:
0.000324
AC XY:
44
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000326
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.000214
AC:
313
AN:
1461764
Hom.:
1
Cov.:
31
AF XY:
0.000232
AC XY:
169
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000190
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.000387
AC:
59
AN:
152314
Hom.:
0
Cov.:
32
AF XY:
0.000349
AC XY:
26
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000482
Hom.:
1
Bravo
AF:
0.000635
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000321
AC:
39
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000654
EpiControl
AF:
0.00101

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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 31, 2024Observed 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2022This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 13, 2021- -
See cases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterDec 20, 2021ACMG categories: PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.32
T;.;T;.;.;T;.;.
Eigen
Benign
0.069
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.035
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
M;.;.;.;.;.;.;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.31
N;N;.;N;.;.;.;.
REVEL
Benign
0.062
Sift
Benign
0.25
T;T;.;T;.;.;.;.
Sift4G
Benign
0.22
T;T;T;T;.;.;.;.
Polyphen
0.83
P;.;.;.;.;.;.;.
Vest4
0.40
MVP
0.36
MPC
0.38
ClinPred
0.066
T
GERP RS
4.0
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.19
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs141983717; hg19: chr3-49141355; COSMIC: COSV60276729; COSMIC: COSV60276729; API