chr3-49098967-T-A

Variant names:

• chr3-49098967-T-A
• rs372524045
• NM_005051.3:c.1781A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005051.3(QARS1):​c.1781A>T​(p.Asn594Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N594T) has been classified as Uncertain significance.

• 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: 5.75
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	NM_005051.3	MANE Select	c.1781A>T	p.Asn594Ile	missense	Exon 19 of 24	NP_005042.1
	QARS1	NM_001272073.2		c.1748A>T	p.Asn583Ile	missense	Exon 19 of 24	NP_001259002.1
	QARS1	NR_073590.2		n.1756A>T		non_coding_transcript_exon	Exon 19 of 24

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.1781A>T	p.Asn594Ile	missense	Exon 19 of 24	ENSP00000307567.6
	QARS1	ENST00000464962.6	TSL:1	c.1346A>T	p.Asn449Ile	missense	Exon 18 of 23	ENSP00000489011.1
	QARS1	ENST00000414533.5	TSL:2	c.1748A>T	p.Asn583Ile	missense	Exon 19 of 24	ENSP00000390015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.061	T
Polyphen		0.92	P
Vest4		0.73
MutPred		0.58		Loss of catalytic residue at N594 (P = 0.0024)
MVP		0.52
MPC		0.92
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.57
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs372524045; hg19: chr3-49136400;