chr3-49099233-T-C

Position:

• chr3-49099233-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005051.3(QARS1):​c.1635A>G​(p.Gln545=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,614,086 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (15 hom.)
• Consequence: QARS1 NM_005051.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.95

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-49099233-T-C is Benign according to our data. Variant chr3-49099233-T-C is described in ClinVar as [Benign]. Clinvar id is 240091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49099233-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00659 (1003/152248) while in subpopulation AFR AF= 0.0226 (939/41548). AF 95% confidence interval is 0.0214. There are 11 homozygotes in gnomad4. There are 485 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QARS1	NM_005051.3	c.1635A>G	p.Gln545=	synonymous_variant	18/24	ENST00000306125.12
QARS1	NM_001272073.2	c.1602A>G	p.Gln534=	synonymous_variant	18/24
QARS1	XM_017006965.3	c.1635A>G	p.Gln545=	synonymous_variant	18/23
QARS1	NR_073590.2	n.1610A>G		non_coding_transcript_exon_variant	18/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12	c.1635A>G	p.Gln545=	synonymous_variant	18/24	1	NM_005051.3	P1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1003 AN: 152130 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00196 AC: 492 AN: 251424 Hom.: 9 AF XY: 0.00152 AC XY: 207 AN XY: 135886

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00163

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000742 AC: 1085 AN: 1461838 Hom.: 15 Cov.: 35 AF XY: 0.000682 AC XY: 496 AN XY: 727216

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152248 Hom.: 11 Cov.: 32 AF XY: 0.00652 AC XY: 485 AN XY: 74430

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00289 Hom.: 0

Bravo AF: 0.00739

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 21, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.9
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs113144521; hg19: chr3-49136666;