Genetic Variant QARS1:c.-273C>T (chr3-49104426-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000464962.6(QARS1):c.-273C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,224 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 28 hom. )

Consequence

QARS1
ENST00000464962.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.53

Publications

3 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: ClinGen, Orphanet, G2P
microcephaly-short stature-intellectual disability-facial dysmorphism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

QARS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000464962.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 3-49104426-G-A is Benign according to our data. Variant chr3-49104426-G-A is described in ClinVar as Benign. ClinVar VariationId is 381869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00216 (329/152360) while in subpopulation EAS AF = 0.0162 (84/5186). AF 95% confidence interval is 0.0134. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000464962.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
QARS1	NM_005051.3	MANE Select	c.163C>T	p.Leu55Leu	synonymous	Exon 2 of 24	NP_005042.1	P47897-1
QARS1	NM_001272073.2		c.163C>T	p.Leu55Leu	synonymous	Exon 2 of 24	NP_001259002.1	P47897-2
QARS1	NR_073590.2		n.187C>T		non_coding_transcript_exon	Exon 2 of 24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
QARS1	ENST00000464962.6	TSL:1	c.-273C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000489011.1	B4DDN1
QARS1	ENST00000306125.12	TSL:1 MANE Select	c.163C>T	p.Leu55Leu	synonymous	Exon 2 of 24	ENSP00000307567.6	P47897-1
QARS1	ENST00000464962.6	TSL:1	c.-273C>T		5_prime_UTR	Exon 1 of 23	ENSP00000489011.1	B4DDN1

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00366

AC:

921

AN:

251440

AF XY:

0.00294

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.0167

Gnomad ASJ exome

AF:

0.00486

Gnomad EAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00144

AC:

2107

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

983

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.0169

AC:

756

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

128

AN:

26136

East Asian (EAS)

AF:

0.0228

AC:

904

AN:

39700

South Asian (SAS)

AF:

0.000452

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000175

AC:

195

AN:

1112004

Other (OTH)

AF:

0.00108

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00216

AC:

329

AN:

152360

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41586

American (AMR)

AF:

0.0110

AC:

169

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.00267

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (1)

QARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.9

(source)

DANN

Benign

0.81

PhyloP100

3.5

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over