NM_005051.3:c.25C>T

Variant names:

• chr3-49104709-G-A
• NM_005051.3:c.25C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005051.3(QARS1):​c.25C>T​(p.Leu9Phe) 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. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QARS1	NM_005051.3	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 24		NP_001259002.1
QARS1	XM_017006965.3	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 23		XP_016862454.2
QARS1	NR_073590.2	n.49C>T		non_coding_transcript_exon_variant	Exon 1 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.25C>T	p.Leu9Phe	missense_variant	Exon 1 of 24	1	NM_005051.3	ENSP00000307567.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460462 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 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: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;T;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	N;N;.;D;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D;.;D;.;.;.
Sift4G	Uncertain	0.0080	D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.43
MutPred		0.72		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		0.63
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;