rs1060502308

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Synonymous variant affecting the same amino acid position (i.e. V493V) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

QARS1 Gene-Disease associations (from GenCC):

• diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• microcephaly-short stature-intellectual disability-facial dysmorphism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005051.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	NM_005051.3	MANE Select	c.1478T>A	p.Val493Asp	missense	Exon 16 of 24	NP_005042.1
	QARS1	NM_001272073.2		c.1445T>A	p.Val482Asp	missense	Exon 16 of 24	NP_001259002.1
	QARS1	NR_073590.2		n.1453T>A		non_coding_transcript_exon	Exon 16 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.1478T>A	p.Val493Asp	missense	Exon 16 of 24	ENSP00000307567.6
	QARS1	ENST00000464962.6	TSL:1	c.1043T>A	p.Val348Asp	missense	Exon 15 of 23	ENSP00000489011.1
	QARS1	ENST00000965966.1		c.1601T>A	p.Val534Asp	missense	Exon 16 of 24	ENSP00000636025.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.0028	T
MutationAssessor	Pathogenic	4.4	H
PhyloP100		8.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.59		Loss of stability (P = 0.0549)
MVP		0.80
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1060502308; hg19: chr3-49136991;