rs141983717

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_005051.3(QARS1):c.316G>A(p.Asp106Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00023 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

QARS1
NM_005051.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.77

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
microcephaly-short stature-intellectual disability-facial dysmorphism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

QARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035427123).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000387 (59/152314) while in subpopulation AMR AF = 0.00137 (21/15300). AF 95% confidence interval is 0.000919. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
QARS1	NM_005051.3 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 3 of 24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2 link	c.283G>A	p.Asp95Asn	missense_variant	Exon 3 of 24		NP_001259002.1
QARS1	XM_017006965.3 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 3 of 23		XP_016862454.2
QARS1	NR_073590.2 link	n.291G>A		non_coding_transcript_exon_variant	Exon 3 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12 link	c.316G>A	p.Asp106Asn	missense_variant	Exon 3 of 24	1	NM_005051.3	ENSP00000307567.6

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000275

AC:

AN:

251280

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000214

AC:

313

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000190

AC:

211

AN:

1112006

Other (OTH)

AF:

0.000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000387

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41566

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000635

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 31, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in heterozygous state in an individual with neuronal seroid lipofuscinosis, epilepsy, and vermis hypoplasia, who also harbored a heterozygous variant in CNTNAP2 (PMID: 33528079); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25888430, 34406647, 25471517, 33528079, Hussein2023[Preprint]) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Uncertain:2

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 106 of the QARS protein (p.Asp106Asn). This variant is present in population databases (rs141983717, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 409237). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Uncertain:1

Dec 20, 2021

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM2 -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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

0.081

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.32

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

Eigen

Benign

0.069

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.035

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

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

PhyloP100

3.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.31

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

REVEL

Benign

0.062

Sift

Benign

0.25

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

Sift4G

Benign

0.22

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

Polyphen

0.83

P;.;.;.;.;.;.;.

Vest4

0.40

MVP

0.36

MPC

0.38

ClinPred

0.066

GERP RS

4.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.19

gMVP

0.36

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over