3-49104709-G-T

Position:

chr3-49104709-G-T

Variant summary

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

The ENST00000306125.12(QARS1):c.25C>A(p.Leu9Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00206 in 1,612,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. L9V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

QARS1
ENST00000306125.12 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.21

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014008164).

BP6

Variant 3-49104709-G-T is Benign according to our data. Variant chr3-49104709-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384247.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=4}. Variant chr3-49104709-G-T is described in Lovd as [Benign]. Variant chr3-49104709-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00213 (324/152372) while in subpopulation AMR AF= 0.00287 (44/15310). AF 95% confidence interval is 0.0023. There are 2 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
QARS1	NM_005051.3 linkuse as main transcript	c.25C>A	p.Leu9Ile	missense_variant	1/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2 linkuse as main transcript	c.25C>A	p.Leu9Ile	missense_variant	1/24		NP_001259002.1
QARS1	XM_017006965.3 linkuse as main transcript	c.25C>A	p.Leu9Ile	missense_variant	1/23		XP_016862454.2
QARS1	NR_073590.2 linkuse as main transcript	n.49C>A		non_coding_transcript_exon_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12 linkuse as main transcript	c.25C>A	p.Leu9Ile	missense_variant	1/24	1	NM_005051.3	ENSP00000307567	P1	P47897-1

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00266

AC:

662

AN:

248470

Hom.:

AF XY:

0.00275

AC XY:

371

AN XY:

134772

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00925

Gnomad NFE exome

AF:

0.00310

Gnomad OTH exome

AF:

0.00379

GnomAD4 exome

AF:

0.00205

AC:

2995

AN:

1460458

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

1491

AN XY:

726316

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.00936

Gnomad4 NFE exome

AF:

0.00199

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00213

AC:

324

AN:

152372

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00287

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00838

Gnomad4 NFE

AF:

0.00262

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00294

AC:

357

EpiCase

AF:

0.00245

EpiControl

AF:

0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	QARS NM_005051.2 exon 1 p.Leu9Ile (c.25C>A): This variant has not been reported in the literature but is present in 0.8% (89/10620) of Finnish alleles including 1 homozygote, as well as 1 homozygote in the South Asian population in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-49104709-G-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:384247) with classifications ranging from Benign to Variant of Uncertain Significance. Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly, progressive, seizures, and cerebral and cerebellar atrophy (MIM#615760). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of microcephaly, progressive, seizures, and cerebral and cerebellar atrophy (MIM#615760) (gnomAD v2: 735 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions but high conservation. (I) 0600 - Variant is located in the annotated glutaminyl-tRNA synthetase, non-specific RNA binding region part 1 (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. The variant has previously been classified as both a VUS and likely benign, but most recently as benign (ClinVar). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

QARS1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;T;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;T;D;D;D;D;D

MetaRNN

Benign

0.014

T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

M;M;.;.;.;.;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N;.;N;.;.;.

REVEL

Benign

0.26

Sift

Uncertain

0.0050

D;D;.;D;.;.;.

Sift4G

Uncertain

0.015

D;D;D;D;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.42

MVP

0.46

MPC

1.0

ClinPred

0.039

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.19

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