rs1060502308

Variant names:

• chr3-49099558-A-T
• rs1060502308
• NM_005051.3:c.1478T>A

Variant summary

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

The NM_005051.3(QARS1):​c.1478T>A​(p.Val493Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

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, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QARS1	NM_005051.3	c.1478T>A	p.Val493Asp	missense_variant	Exon 16 of 24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.1445T>A	p.Val482Asp	missense_variant	Exon 16 of 24		NP_001259002.1
QARS1	XM_017006965.3	c.1478T>A	p.Val493Asp	missense_variant	Exon 16 of 23		XP_016862454.2
QARS1	NR_073590.2	n.1453T>A		non_coding_transcript_exon_variant	Exon 16 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.1478T>A	p.Val493Asp	missense_variant	Exon 16 of 24	1	NM_005051.3	ENSP00000307567.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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

Nov 30, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a QARS-related disease. This sequence change replaces valine with aspartic acid at codon 493 of the QARS protein (p.Val493Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	.;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	-0.0028	T
MutationAssessor	Pathogenic	4.4	.;H;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.0	D;D;D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.89, 0.88, 0.90
MutPred		0.59		.;Loss of stability (P = 0.0549);.;.;
MVP		0.80
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

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: rs1060502308; hg19: chr3-49136991;