chr3-49096097-A-AAGG

Variant names:

• chr3-49096097-A-AAGG
• rs1166032765
• NM_005051.3:c.2278-21_2278-19dupCCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_005051.3(QARS1):​c.2278-21_2278-19dupCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: QARS1 NM_005051.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-49096097-A-AAGG is Benign according to our data. Variant chr3-49096097-A-AAGG is described in ClinVar as Likely_benign. ClinVar VariationId is 1532106.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2278-21_2278-19dupCCT		intron	N/A	NP_005042.1	P47897-1
	QARS1	NM_001272073.2		c.2245-21_2245-19dupCCT		intron	N/A	NP_001259002.1	P47897-2
	QARS1	NR_073590.2		n.2253-21_2253-19dupCCT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.2278-19_2278-18insCCT		intron	N/A	ENSP00000307567.6	P47897-1
	QARS1	ENST00000464962.6	TSL:1	c.1843-19_1843-18insCCT		intron	N/A	ENSP00000489011.1	B4DDN1
	QARS1	ENST00000965966.1		c.2401-19_2401-18insCCT		intron	N/A	ENSP00000636025.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461008 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726770

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111694

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1166032765; hg19: chr3-49133530;