chr3-49103687-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_005051.3(QARS1):​c.395G>C​(p.Arg132Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

QARS1
NM_005051.3 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.296
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 -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.006790161).
BP6
Variant 3-49103687-C-G is Benign according to our data. Variant chr3-49103687-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415519.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000723 (11/152216) while in subpopulation AMR AF= 0.00072 (11/15284). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
QARS1NM_005051.3 linkc.395G>C p.Arg132Thr missense_variant Exon 4 of 24 ENST00000306125.12 NP_005042.1 P47897-1B7Z840
QARS1NM_001272073.2 linkc.362G>C p.Arg121Thr missense_variant Exon 4 of 24 NP_001259002.1 P47897-2B7Z840
QARS1XM_017006965.3 linkc.395G>C p.Arg132Thr missense_variant Exon 4 of 23 XP_016862454.2
QARS1NR_073590.2 linkn.370G>C non_coding_transcript_exon_variant Exon 4 of 24

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
QARS1ENST00000306125.12 linkc.395G>C p.Arg132Thr missense_variant Exon 4 of 24 1 NM_005051.3 ENSP00000307567.6 P47897-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000760
AC:
190
AN:
250092
Hom.:
0
AF XY:
0.000466
AC XY:
63
AN XY:
135282
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00548
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000138
AC:
201
AN:
1461454
Hom.:
0
Cov.:
31
AF XY:
0.0000963
AC XY:
70
AN XY:
726992
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000720
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000755
Hom.:
0
Bravo
AF:
0.000283
ExAC
AF:
0.000675
AC:
82

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Benign:2
May 29, 2025
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BP4 -

Dec 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Feb 28, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1
Aug 17, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
14
DANN
Benign
0.78
DEOGEN2
Benign
0.40
T;.;T;.;.;T;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.31
N
LIST_S2
Uncertain
0.86
D;D;D;D;D;D;D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.0068
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.66
N;.;.;.;.;.;.;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.9
N;N;.;N;.;.;.;.
REVEL
Benign
0.035
Sift
Benign
0.30
T;T;.;T;.;.;.;.
Sift4G
Benign
0.26
T;T;T;T;.;.;.;.
Polyphen
0.038
B;.;.;.;.;.;.;.
Vest4
0.38
MutPred
0.32
Loss of MoRF binding (P = 0.1376);.;Loss of MoRF binding (P = 0.1376);.;Loss of MoRF binding (P = 0.1376);.;.;.;
MVP
0.30
MPC
0.52
ClinPred
0.016
T
GERP RS
-1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.16
gMVP
0.23

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: rs530494890; hg19: chr3-49141120; API