chr3-49100222-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_005051.3(QARS1):c.1132C>G(p.Arg378Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

QARS1
NM_005051.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-49100222-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 598952.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005051.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
QARS1	NM_005051.3	MANE Select	c.1132C>G	p.Arg378Gly	missense	Exon 13 of 24	NP_005042.1
QARS1	NM_001272073.2		c.1099C>G	p.Arg367Gly	missense	Exon 13 of 24	NP_001259002.1
QARS1	NR_073590.2		n.1107C>G		non_coding_transcript_exon	Exon 13 of 24

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
QARS1	ENST00000306125.12	TSL:1 MANE Select	c.1132C>G	p.Arg378Gly	missense	Exon 13 of 24	ENSP00000307567.6
QARS1	ENST00000464962.6	TSL:1	c.697C>G	p.Arg233Gly	missense	Exon 12 of 23	ENSP00000489011.1
QARS1	ENST00000414533.5	TSL:2	c.1099C>G	p.Arg367Gly	missense	Exon 13 of 24	ENSP00000390015.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250996

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Sep 13, 2019

Breda Genetics srl

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant c.1132C>G (p.Arg378Gly) is reported with an estimated allele frequency of 0.000003984 in gnomAD exomes, with no homozygous individuals reported. The nucleotide position is conserved across 35 mammalian species (GERP RS: 5.12). In silico analysis indicates that the variant might be damaging. Another missense variant, c.1132C>T (p.Arg378Cys), that falls at the same coding position, is reported in Clinvar as likely pathogenic (Variation ID: 598952). Based on ACMG variant interpretation guidelines, we classify this variant as uncertain. However, on the basis of the aforementioned evidence, there is a given likelihood that the variant may actually be pathogenic, even if we cannot exclude that it is a rare benign variant.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.25

MutationAssessor

Pathogenic

4.2

PhyloP100

6.2

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.88

MutPred

0.68

Gain of glycosylation at S383 (P = 0.0241)

MVP

0.60

MPC

1.2

ClinPred

1.0

GERP RS

5.1

PromoterAI

-0.0038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.82

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over