NM_005051.3:c.673C>T

Variant names:

• chr3-49101858-G-A
• rs142517070
• NM_005051.3:c.673C>T
• QARS1 p.Arg225Trp

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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
• Publications: 5 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: Orphanet, G2P, ClinGen
• microcephaly-short stature-intellectual disability-facial dysmorphism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 477843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (287/152334) while in subpopulation NFE AF = 0.0005 (34/68032). AF 95% confidence interval is 0.000367. There are 5 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.673C>T	p.Arg225Trp	missense	Exon 8 of 24	NP_005042.1	P47897-1
	QARS1	NM_001272073.2		c.640C>T	p.Arg214Trp	missense	Exon 8 of 24	NP_001259002.1	P47897-2
	QARS1	NR_073590.2		n.648C>T		non_coding_transcript_exon	Exon 8 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.673C>T	p.Arg225Trp	missense	Exon 8 of 24	ENSP00000307567.6	P47897-1
	QARS1	ENST00000464962.6	TSL:1	c.238C>T	p.Arg80Trp	missense	Exon 7 of 23	ENSP00000489011.1	B4DDN1
	QARS1	ENST00000965966.1		c.796C>T	p.Arg266Trp	missense	Exon 8 of 24	ENSP00000636025.1

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

GnomAD2 exomes AF: 0.00211 AC: 523 AN: 247486 AF XY: 0.00212

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 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

African (AFR) AF: 0.0000599 AC: 2 AN: 33400

American (AMR) AF: 0.0000225 AC: 1 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85996

European-Finnish (FIN) AF: 0.0192 AC: 1026 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000317 AC: 352 AN: 1111176

Other (OTH) AF: 0.000630 AC: 38 AN: 60308

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.018	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.16
gMVP		0.62
Mutation Taster		=92/8	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs142517070; hg19: chr3-49139291; COSMIC: COSV100069708; COSMIC: COSV100069708;