rs144563810

Variant names:

• chr3-49098988-G-A
• rs144563810
• NM_005051.3:c.1760C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005051.3(QARS1):​c.1760C>T​(p.Ser587Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0001 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S587S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: QARS1 NM_005051.3 missense, splice_region
• Scores: Splicing: ADA: 0.02379
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.31
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02154252).
• BP6: Variant 3-49098988-G-A is Benign according to our data. Variant chr3-49098988-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409245.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000545 (83/152204) while in subpopulation AFR AF = 0.00197 (82/41534). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1760C>T	p.Ser587Phe	missense splice_region	Exon 19 of 24	NP_005042.1	P47897-1
	QARS1	NM_001272073.2		c.1727C>T	p.Ser576Phe	missense splice_region	Exon 19 of 24	NP_001259002.1	P47897-2
	QARS1	NR_073590.2		n.1735C>T		splice_region non_coding_transcript_exon	Exon 19 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.1760C>T	p.Ser587Phe	missense splice_region	Exon 19 of 24	ENSP00000307567.6	P47897-1
	QARS1	ENST00000464962.6	TSL:1	c.1325C>T	p.Ser442Phe	missense splice_region	Exon 18 of 23	ENSP00000489011.1	B4DDN1
	QARS1	ENST00000466179.2	TSL:3	c.2C>T	p.Ser1Phe	missense	Exon 1 of 3	ENSP00000489462.1	A0A0U1RRC8

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00198

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251436 AF XY: 0.000125

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1461358 Hom.: 0 Cov.: 34 AF XY: 0.0000564 AC XY: 41 AN XY: 727016

African (AFR) AF: 0.00218 AC: 73 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111538

Other (OTH) AF: 0.0000994 AC: 6 AN: 60372

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74408

African (AFR) AF: 0.00197 AC: 82 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000597

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (1)
-	1	-	not provided (1)
-	-	1	QARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.3
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.097
Sift	Benign	0.043	D
Sift4G	Benign	0.14	T
Polyphen		0.086	B
Vest4		0.33
MVP		0.43
MPC		0.41
ClinPred		0.095	T
GERP RS		4.7
PromoterAI		-0.020	Neutral
Varity_R		0.21
gMVP		0.41
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.32
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

Other links and lift over

dbSNP: rs144563810; hg19: chr3-49136421; COSMIC: COSV60275023; COSMIC: COSV60275023;