rs11539148

Variant names:

• chr3-49101377-T-C
• rs11539148
• NM_005051.3:c.854A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-49101377-T-C
• chr3-49101377-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005051.3(QARS1):​c.854A>G​(p.Asn285Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0547 in 1,613,540 control chromosomes in the GnomAD database, including 2,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (169 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2644 hom.)
• Consequence: QARS1 NM_005051.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.76
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056907833).
• BP6: Variant 3-49101377-T-C is Benign according to our data. Variant chr3-49101377-T-C is described in ClinVar as Benign. ClinVar VariationId is 380108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

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.854A>G	p.Asn285Ser	missense	Exon 10 of 24	NP_005042.1	P47897-1
	QARS1	NM_001272073.2		c.821A>G	p.Asn274Ser	missense	Exon 10 of 24	NP_001259002.1	P47897-2
	QARS1	NR_073590.2		n.829A>G		non_coding_transcript_exon	Exon 10 of 24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QARS1	ENST00000306125.12	TSL:1 MANE Select	c.854A>G	p.Asn285Ser	missense	Exon 10 of 24	ENSP00000307567.6	P47897-1
	QARS1	ENST00000464962.6	TSL:1	c.419A>G	p.Asn140Ser	missense	Exon 9 of 23	ENSP00000489011.1	B4DDN1
	QARS1	ENST00000965966.1		c.977A>G	p.Asn326Ser	missense	Exon 10 of 24	ENSP00000636025.1

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 6062 AN: 152192 Hom.: 169 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0620

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0397 AC: 9981 AN: 251102 AF XY: 0.0401

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0496

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0659

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0563 AC: 82225 AN: 1461230 Hom.: 2644 Cov.: 31 AF XY: 0.0548 AC XY: 39829 AN XY: 726934

African (AFR) AF: 0.00849 AC: 284 AN: 33462

American (AMR) AF: 0.0179 AC: 799 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 1360 AN: 26122

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39692

South Asian (SAS) AF: 0.0145 AC: 1246 AN: 86228

European-Finnish (FIN) AF: 0.0646 AC: 3449 AN: 53412

Middle Eastern (MID) AF: 0.0103 AC: 59 AN: 5756

European-Non Finnish (NFE) AF: 0.0649 AC: 72184 AN: 1111512

Other (OTH) AF: 0.0468 AC: 2828 AN: 60370

GnomAD4 genome AF: 0.0398 AC: 6063 AN: 152310 Hom.: 169 Cov.: 33 AF XY: 0.0389 AC XY: 2897 AN XY: 74468

African (AFR) AF: 0.0109 AC: 453 AN: 41582

American (AMR) AF: 0.0229 AC: 351 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4832

European-Finnish (FIN) AF: 0.0648 AC: 687 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0620 AC: 4219 AN: 68020

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0495 Hom.: 521

Bravo AF: 0.0344

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0682 AC: 263

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.0572 AC: 492

ExAC AF: 0.0390 AC: 4732

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0549

EpiControl AF: 0.0539

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.015
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.19
Sift	Benign	0.27	T
Sift4G	Benign	0.39	T
Polyphen		0.054	B
Vest4		0.45
MPC		0.30
ClinPred		0.040	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.90
Mutation Taster		=73/27	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs11539148; hg19: chr3-49138810; COSMIC: COSV107380589; COSMIC: COSV107380589;