chr3-49099385-G-A

Position:

• chr3-49099385-G-A

Variant summary

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

The NM_005051.3(QARS1):​c.1573C>T​(p.Arg525Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.03

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 (HGNC:):

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, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QARS1	NM_005051.3	c.1573C>T	p.Arg525Trp	missense_variant	17/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.1540C>T	p.Arg514Trp	missense_variant	17/24		NP_001259002.1
QARS1	XM_017006965.3	c.1573C>T	p.Arg525Trp	missense_variant	17/23		XP_016862454.2
QARS1	NR_073590.2	n.1548C>T		non_coding_transcript_exon_variant	17/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.1573C>T	p.Arg525Trp	missense_variant	17/24	1	NM_005051.3	ENSP00000307567.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461868 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

The c.1573C>T (p.R525W) alteration is located in exon 17 (coding exon 17) of the QARS gene. This alteration results from a C to T substitution at nucleotide position 1573, causing the arginine (R) at amino acid position 525 to be replaced by a tryptophan (W). The amino acid is located in a functionally important protein domain:_x000D_ The p.R525W amino acid is located in the catalytic domain which is responsible for the ATP dependent attachment of the amino acid to the enzyme. It is located after the KMSKS motif which binds to ATP. Another missense substitution in the same loop (p.R515Y) was suggested to increase the aggregation of this protein and disrupt aminoacylation activity. However, there is no evidence protein aggregation and function would be affected by a change in position p.R525._x000D_ _x000D_ Structual modeling of this alteration is inconclusive_x000D_ Structural modeling performed in house at Ambry Genetics revealed that the position R525 is in a disordered loop lying in a buried region between the catalytic domain and the codon binding domain. This interfacial is identified to be subject to allosteric effects by (Zhang, 2014). The change R->W is unfavored (BLOSUM62 -3 and the nearby variant (R215W) has been identified to be pathogenic. However, R525W is not significantly destabilizing (-0.35) compared to R215W (10.52). While the variant likely perturbs in folding, structural evidence is not conclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 520898). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 525 of the QARS protein (p.Arg525Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;D
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Pathogenic	4.7	.;H;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D;D;D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.87, 0.83, 0.89
MutPred		0.78		.;Loss of methylation at R525 (P = 0.0396);.;.;
MVP		0.54
MPC		1.1
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.91

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: rs1553751726; hg19: chr3-49136818; COSMIC: COSV60275602; COSMIC: COSV60275602;