rs775642346

chr3-49101907-G-GA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_005051.3(QARS1):c.632-9_632-8insT variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000199 in 1,605,348 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: QARS1 NM_005051.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.76

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-49101907-G-GA is Benign according to our data. Variant chr3-49101907-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 415520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QARS1	NM_005051.3	c.632-9_632-8insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000306125.12
QARS1	NM_001272073.2	c.599-9_599-8insT		splice_polypyrimidine_tract_variant, intron_variant
QARS1	XM_017006965.3	c.632-9_632-8insT		splice_polypyrimidine_tract_variant, intron_variant
QARS1	NR_073590.2	n.607-9_607-8insT		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QARS1	ENST00000306125.12	c.632-9_632-8insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005051.3	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000135 AC: 32 AN: 237326 Hom.: 0 AF XY: 0.000147 AC XY: 19 AN XY: 128880

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000588

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000202 AC: 293 AN: 1453036 Hom.: 1 Cov.: 32 AF XY: 0.000203 AC XY: 147 AN XY: 722554

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.0000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000603

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs775642346; hg19: chr3-49139340;