3-49099156-A-C

Variant names:

• chr3-49099156-A-C
• rs755259427
• NM_005051.3:c.1712T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005051.3(QARS1):​c.1712T>G​(p.Val571Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V571A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.69
• 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: G2P, ClinGen, Orphanet
• microcephaly-short stature-intellectual disability-facial dysmorphism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	NM_005051.3	MANE Select	c.1712T>G	p.Val571Gly	missense	Exon 18 of 24	NP_005042.1
	QARS1	NM_001272073.2		c.1679T>G	p.Val560Gly	missense	Exon 18 of 24	NP_001259002.1
	QARS1	NR_073590.2		n.1687T>G		non_coding_transcript_exon	Exon 18 of 24

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.1712T>G	p.Val571Gly	missense	Exon 18 of 24	ENSP00000307567.6
	QARS1	ENST00000464962.6	TSL:1	c.1277T>G	p.Val426Gly	missense	Exon 17 of 23	ENSP00000489011.1
	QARS1	ENST00000414533.5	TSL:2	c.1679T>G	p.Val560Gly	missense	Exon 18 of 24	ENSP00000390015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.7
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.81		Loss of stability (P = 0.0021)
MVP		0.84
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.030	Neutral
Varity_R		0.97
gMVP		0.97
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs755259427; hg19: chr3-49136589;