chr3-49104709-G-C

Position:

• chr3-49104709-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005051.3(QARS1):​c.25C>G​(p.Leu9Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L9I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QARS1	NM_005051.3	c.25C>G	p.Leu9Val	missense_variant	1/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.25C>G	p.Leu9Val	missense_variant	1/24		NP_001259002.1
QARS1	XM_017006965.3	c.25C>G	p.Leu9Val	missense_variant	1/23		XP_016862454.2
QARS1	NR_073590.2	n.49C>G		non_coding_transcript_exon_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.25C>G	p.Leu9Val	missense_variant	1/24	1	NM_005051.3	ENSP00000307567	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460462 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with QARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the QARS protein (p.Leu9Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;N;.;N;.;.;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D;D;.;D;.;.;.
Sift4G	Benign	0.077	T;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.41
MutPred		0.71		Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);Gain of glycosylation at S6 (P = 0.0155);
MVP		0.55
MPC		0.98
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49142142;