3-49104464-T-A

Position:

• chr3-49104464-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005051.3(QARS1):​c.125A>T​(p.Gln42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. Q42P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.467

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08595523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QARS1	NM_005051.3	c.125A>T	p.Gln42Leu	missense_variant	2/24	ENST00000306125.12
QARS1	NM_001272073.2	c.125A>T	p.Gln42Leu	missense_variant	2/24
QARS1	XM_017006965.3	c.125A>T	p.Gln42Leu	missense_variant	2/23
QARS1	NR_073590.2	n.149A>T		non_coding_transcript_exon_variant	2/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12	c.125A>T	p.Gln42Leu	missense_variant	2/24	1	NM_005051.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;.;T;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N;N;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N;.;N;.;.;.
REVEL	Benign	0.080
Sift	Benign	0.30	T;T;.;T;.;.;.
Sift4G	Benign	0.30	T;T;T;T;.;.;.
Polyphen		0.067	B;.;.;.;.;.;.
Vest4		0.31
MutPred		0.47		Gain of glycosylation at T43 (P = 0.0376);Gain of glycosylation at T43 (P = 0.0376);Gain of glycosylation at T43 (P = 0.0376);Gain of glycosylation at T43 (P = 0.0376);Gain of glycosylation at T43 (P = 0.0376);.;.;
MVP		0.25
MPC		0.32
ClinPred		0.29	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs546520104; hg19: chr3-49141897;