rs142517070

chr3-49101858-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005051.3(QARS1):c.673C>T(p.Arg225Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,612,400 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (15 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.27

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00934428).
• BP6: Variant 3-49101858-G-A is Benign according to our data. Variant chr3-49101858-G-A is described in ClinVar as [Benign]. Clinvar id is 477843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49101858-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QARS1	NM_005051.3	c.673C>T	p.Arg225Trp	missense_variant	8/24	ENST00000306125.12
QARS1	NM_001272073.2	c.640C>T	p.Arg214Trp	missense_variant	8/24
QARS1	XM_017006965.3	c.673C>T	p.Arg225Trp	missense_variant	8/23
QARS1	NR_073590.2	n.648C>T		non_coding_transcript_exon_variant	8/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12	c.673C>T	p.Arg225Trp	missense_variant	8/24	1	NM_005051.3	P1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152216 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00211 AC: 523 AN: 247486 Hom.: 9 AF XY: 0.00212 AC XY: 284 AN XY: 133888

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000973 AC: 1421 AN: 1460066 Hom.: 15 Cov.: 32 AF XY: 0.000920 AC XY: 668 AN XY: 726230

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152334 Hom.: 5 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.;T;T;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
MetaRNN	Benign	0.0093	T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;.;.;.;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.016	D;D;.;.;.;D;.
Sift4G	Uncertain	0.018	D;D;D;T;.;T;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.73
MVP		0.55
MPC		1.1
ClinPred		0.060	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.16
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142517070; hg19: chr3-49139291; COSMIC: COSV100069708; COSMIC: COSV100069708;