chr3-49101377-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005051.3(QARS1):c.854A>G(p.Asn285Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0547 in 1,613,540 control chromosomes in the GnomAD database, including 2,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 169 hom., cov: 33)

Exomes 𝑓: 0.056 ( 2644 hom. )

Consequence

QARS1
NM_005051.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.76

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056907833).

BP6

Variant 3-49101377-T-C is Benign according to our data. Variant chr3-49101377-T-C is described in ClinVar as Benign. ClinVar VariationId is 380108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QARS1	NM_005051.3 link	c.854A>G	p.Asn285Ser	missense_variant	Exon 10 of 24	ENST00000306125.12	NP_005042.1	P47897-1B7Z840
QARS1	NM_001272073.2 link	c.821A>G	p.Asn274Ser	missense_variant	Exon 10 of 24		NP_001259002.1	P47897-2B7Z840
QARS1	XM_017006965.3 link	c.854A>G	p.Asn285Ser	missense_variant	Exon 10 of 23		XP_016862454.2
QARS1	NR_073590.2 link	n.829A>G		non_coding_transcript_exon_variant	Exon 10 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12 link	c.854A>G	p.Asn285Ser	missense_variant	Exon 10 of 24	1	NM_005051.3	ENSP00000307567.6		P47897-1

Frequencies

GnomAD3 genomes

AF:

0.0398

AC:

6062

AN:

152192

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0528

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0648

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0620

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0397

AC:

9981

AN:

251102

AF XY:

0.0401

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0182

Gnomad ASJ exome

AF:

0.0496

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0659

Gnomad NFE exome

AF:

0.0581

Gnomad OTH exome

AF:

0.0448

GnomAD4 exome

AF:

0.0563

AC:

82225

AN:

1461230

Hom.:

2644

Cov.:

AF XY:

0.0548

AC XY:

39829

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.00849

AC:

284

AN:

33462

American (AMR)

AF:

0.0179

AC:

799

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0521

AC:

1360

AN:

26122

East Asian (EAS)

AF:

0.000403

AC:

AN:

39692

South Asian (SAS)

AF:

0.0145

AC:

1246

AN:

86228

European-Finnish (FIN)

AF:

0.0646

AC:

3449

AN:

53412

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0649

AC:

72184

AN:

1111512

Other (OTH)

AF:

0.0468

AC:

2828

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3672

7344

11015

14687

18359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2656

5312

7968

10624

13280

<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:

0.0398

AC:

6063

AN:

152310

Hom.:

169

Cov.:

AF XY:

0.0389

AC XY:

2897

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0109

AC:

453

AN:

41582

American (AMR)

AF:

0.0229

AC:

351

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0528

AC:

183

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0149

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0648

AC:

687

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0620

AC:

4219

AN:

68020

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

298

596

894

1192

1490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0495

Hom.:

521

Bravo

AF:

0.0344

TwinsUK

AF:

0.0618

AC:

229

ALSPAC

AF:

0.0682

AC:

263

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.0572

AC:

492

ExAC

AF:

0.0390

AC:

4732

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0549

EpiControl

AF:

0.0539

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 17, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 04, 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

0.22

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

D;.;D;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.015

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T;T

MetaRNN

Benign

0.0057

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.4

D;D;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.27

T;T;.;.;.

Sift4G

Benign

0.39

T;T;T;.;D

Polyphen

0.054

B;.;.;.;.

Vest4

0.45

MPC

0.30

ClinPred

0.040

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.90

Mutation Taster

=73/27

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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