rs144563810

Variant summary

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

The NM_005051.3(QARS1):c.1760C>T(p.Ser587Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0001 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S587S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

QARS1
NM_005051.3 missense, splice_region

Scores

Splicing: ADA: 0.02379

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.31

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02154252).

BP6

Variant 3-49098988-G-A is Benign according to our data. Variant chr3-49098988-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409245.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000545 (83/152204) while in subpopulation AFR AF= 0.00197 (82/41534). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
QARS1	NM_005051.3 linkuse as main transcript	c.1760C>T	p.Ser587Phe	missense_variant, splice_region_variant	19/24	ENST00000306125.12
QARS1	NM_001272073.2 linkuse as main transcript	c.1727C>T	p.Ser576Phe	missense_variant, splice_region_variant	19/24
QARS1	XM_017006965.3 linkuse as main transcript	c.1760C>T	p.Ser587Phe	missense_variant, splice_region_variant	19/23
QARS1	NR_073590.2 linkuse as main transcript	n.1735C>T		splice_region_variant, non_coding_transcript_exon_variant	19/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12 linkuse as main transcript	c.1760C>T	p.Ser587Phe	missense_variant, splice_region_variant	19/24	1	NM_005051.3	P1	P47897-1

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000479

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251436

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.00

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:

0.0000994

GnomAD4 genome

AF:

0.000545

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00

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:

0.000474

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000597

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

QARS1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.044

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.89

D;D

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.4

D;D;D;.;.

REVEL

Benign

0.097

Sift

Benign

0.043

D;T;T;.;.

Sift4G

Benign

0.14

T;T;T;T;D

Polyphen

0.086

.;B;.;.;.

Vest4

0.33, 0.40, 0.38

MVP

0.43

MPC

0.41

ClinPred

0.095

GERP RS

4.7

Varity_R

0.21

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.024

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.010

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