chr3-49100222-G-A

Position:

chr3-49100222-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The ENST00000306125.12(QARS1):c.1132C>T(p.Arg378Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

QARS1
ENST00000306125.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.17

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]

QARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-49100222-G-A is Pathogenic according to our data. Variant chr3-49100222-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 598952.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
QARS1	NM_005051.3 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	13/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	13/24		NP_001259002.1
QARS1	XM_017006965.3 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	13/23		XP_016862454.2
QARS1	NR_073590.2 linkuse as main transcript	n.1107C>T		non_coding_transcript_exon_variant	13/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	13/24	1	NM_005051.3	ENSP00000307567	P1	P47897-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

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:

0.0000797

AC:

AN:

250996

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 17, 2022	This variant was identified as compound heterozygous with NM_005051.3:c.1567C>T._x000D_ Criteria applied: PM3_STR, PM2_SUP, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the QARS protein (p.Arg378Cys). This variant is present in population databases (rs185476065, gnomAD 0.07%). This missense change has been observed in individuals with QARS-related conditions (PMID: 30755392, 31618474). ClinVar contains an entry for this variant (Variation ID: 598952). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on QARS protein function. 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. -

Ectopic tissue;C0036572:Seizure;C0038379:Strabismus;C0344482:Hypoplasia of the corpus callosum;C0575802:Small hand;C0917801:Insomnia;C1848673:Short foot;C3553450:Profound global developmental delay;C4021798:Abnormal nonverbal communicative behavior;C4048268:Cerebral visual impairment;C4551563:Microcephaly

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

QARS1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2023

The QARS1 c.1132C>T variant is predicted to result in the amino acid substitution p.Arg378Cys. This variant has been reported in the compound heterozygous state in multiple individuals with epilepsy (Table S2 in Burgess et al. 2019. PubMed ID: 31618474; Table S2 in Ji et al. 2019. PubMed ID: 30755392; Chan et al. 2022. PubMed ID: 34774383). A functional study found that the p.Arg378Cys substitution decreases protein solubility (Chan et al. 2022. PubMed ID: 34774383). This variant is reported in 0.070% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-49137655-G-A). Given the evidence, we interpret c.1132C>T (p.Arg378Cys) as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2022

Published functional studies demonstrate a damaging effect on aminoacylation and QARS solubility (Chan et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a second QARS variant on the opposite allele (in trans) in children with seizures, developmental delay, microcephaly, and brain malformations in published literature (Burgess et al., 2019; Chan et al., 2022; Ji et al., 2019); This variant is associated with the following publications: (PMID: 25471517, 34774383, 31618474, 30755392) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.0048

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Uncertain

0.032

MutationAssessor

Pathogenic

4.6

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-8.0

D;D;.

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.87

MVP

0.65

MPC

1.2

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over