3-49099416-T-C

Position:

• chr3-49099416-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.1542A>G​(p.Pro514Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,118 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: QARS1 NM_005051.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.60

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=-0.83).
• BP6: Variant 3-49099416-T-C is Benign according to our data. Variant chr3-49099416-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 388044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49099416-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000118 (172/1461894) while in subpopulation AMR AF= 0.000671 (30/44724). AF 95% confidence interval is 0.000483. There are 2 homozygotes in gnomad4_exome. There are 92 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QARS1	NM_005051.3	c.1542A>G	p.Pro514Pro	synonymous_variant	17/24	ENST00000306125.12	NP_005042.1
QARS1	NM_001272073.2	c.1509A>G	p.Pro503Pro	synonymous_variant	17/24		NP_001259002.1
QARS1	XM_017006965.3	c.1542A>G	p.Pro514Pro	synonymous_variant	17/23		XP_016862454.2
QARS1	NR_073590.2	n.1517A>G		non_coding_transcript_exon_variant	17/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QARS1	ENST00000306125.12	c.1542A>G	p.Pro514Pro	synonymous_variant	17/24	1	NM_005051.3	ENSP00000307567.6

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251480 Hom.: 1 AF XY: 0.000162 AC XY: 22 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461894 Hom.: 2 Cov.: 35 AF XY: 0.000127 AC XY: 92 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74442

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.000136

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs370232570; hg19: chr3-49136849;