rs144092780

Positions:

• chr3-49099610-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005051.3(QARS1):​c.1426G>A​(p.Val476Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,614,166 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.13

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010393411).
• BP6: Variant 3-49099610-C-T is Benign according to our data. Variant chr3-49099610-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380083.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr3-49099610-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (246/152304) while in subpopulation NFE AF= 0.00275 (187/68032). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QARS1	NM_005051.3	c.1426G>A	p.Val476Ile	missense_variant	16/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.1393G>A	p.Val465Ile	missense_variant	16/24		NP_001259002.1
QARS1	XM_017006965.3	c.1426G>A	p.Val476Ile	missense_variant	16/23		XP_016862454.2
QARS1	NR_073590.2	n.1401G>A		non_coding_transcript_exon_variant	16/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.1426G>A	p.Val476Ile	missense_variant	16/24	1	NM_005051.3	ENSP00000307567	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00162 AC: 408 AN: 251388 Hom.: 1 AF XY: 0.00169 AC XY: 230 AN XY: 135858

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00211 AC: 3086 AN: 1461862 Hom.: 7 Cov.: 35 AF XY: 0.00208 AC XY: 1510 AN XY: 727232

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74482

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 2

Bravo AF: 0.00147

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	QARS1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2021	This variant is associated with the following publications: (PMID: 28620870, 27572814) -

QARS1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.49
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.18	N;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.060	N;N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.88	T;T;T
Polyphen		0.70	P;.;.
Vest4		0.26
MVP		0.14
MPC		0.72
ClinPred		0.018	T
GERP RS		4.1
Varity_R		0.066
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs144092780; hg19: chr3-49137043;