chr3-49099610-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005051.3(QARS1):c.1426G>A(p.Val476Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,614,166 control chromosomes in the GnomAD database, including 7 homozygotes. 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: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

QARS1
NM_005051.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.13

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:

MIR6890 (HGNC:49990): (microRNA 6890) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6890 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010393411).

BP6

Variant 3-49099610-C-T is Benign according to our data. Variant chr3-49099610-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380083.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr3-49099610-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (246/152304) while in subpopulation NFE AF= 0.00275 (187/68032). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QARS1	NM_005051.3 link	c.1426G>A	p.Val476Ile	missense_variant	Exon 16 of 24	ENST00000306125.12	NP_005042.1	P47897-1B7Z840

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12 link	c.1426G>A	p.Val476Ile	missense_variant	Exon 16 of 24	1	NM_005051.3	ENSP00000307567.6		P47897-1

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

246

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00162

AC:

408

AN:

251388

Hom.:

AF XY:

0.00169

AC XY:

230

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00211

AC:

3086

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1510

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00413

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00234

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00238

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.00162

AC:

246

AN:

152304

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00248

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

QARS1: BP4 -

Feb 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28620870, 27572814) -

QARS1-related disorder

Benign:1

Nov 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.25

T;.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0097

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.18

N;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

0.060

N;N;.

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.88

T;T;T

Polyphen

0.70

P;.;.

Vest4

0.26

MVP

0.14

MPC

0.72

ClinPred

0.018

GERP RS

4.1

Varity_R

0.066

gMVP

0.35

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.

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