chr3-49099156-A-C

Position:

• chr3-49099156-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000306125.12(QARS1):​c.1712T>G​(p.Val571Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V571A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: QARS1 ENST00000306125.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.69

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QARS1	NM_005051.3	c.1712T>G	p.Val571Gly	missense_variant	18/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.1679T>G	p.Val560Gly	missense_variant	18/24		NP_001259002.1
QARS1	XM_017006965.3	c.1712T>G	p.Val571Gly	missense_variant	18/23		XP_016862454.2
QARS1	NR_073590.2	n.1687T>G		non_coding_transcript_exon_variant	18/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.1712T>G	p.Val571Gly	missense_variant	18/24	1	NM_005051.3	ENSP00000307567	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	4.3	.;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.7	D;D;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.55, 0.55, 0.65
MutPred		0.81		.;Loss of stability (P = 0.0021);.;.;
MVP		0.84
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.97

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: rs755259427; hg19: chr3-49136589;