rs1307590384

Positions:

• chr3-49101373-G-T

Variant summary

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

The NM_005051.3(QARS1):​c.858C>A​(p.Phe286Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. F286F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.50

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	UniProt
QARS1	NM_005051.3	c.858C>A	p.Phe286Leu	missense_variant	10/24	ENST00000306125.12
QARS1	NM_001272073.2	c.825C>A	p.Phe275Leu	missense_variant	10/24
QARS1	XM_017006965.3	c.858C>A	p.Phe286Leu	missense_variant	10/23
QARS1	NR_073590.2	n.833C>A		non_coding_transcript_exon_variant	10/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12	c.858C>A	p.Phe286Leu	missense_variant	10/24	1	NM_005051.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461402 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;.;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N;N;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.17	T;T;.;.;.
Sift4G	Benign	0.36	T;T;T;.;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.86
MutPred		0.79		Loss of methylation at K282 (P = 0.1205);.;.;.;.;
MVP		0.37
MPC		1.1
ClinPred		0.87	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs1307590384; hg19: chr3-49138806;