rs556155

chr9-92223355-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002161.6(IARS1):c.3544A>G(p.Lys1182Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,609,906 control chromosomes in the GnomAD database, including 22,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1833 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21017 hom.)
• Consequence: IARS1 NM_002161.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.208

Genes affected

IARS1 (HGNC:5330): (isoleucyl-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. Isoleucine-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family and has been identified as a target of autoantibodies in the autoimmune disease polymyositis/dermatomyositis. Alternatively spliced transcript variants have been found. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052803755).
• BP6: Variant 9-92223355-T-C is Benign according to our data. Variant chr9-92223355-T-C is described in ClinVar as [Benign]. Clinvar id is 1285248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS1	NM_002161.6	c.3544A>G	p.Lys1182Glu	missense_variant	32/34	ENST00000443024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS1	ENST00000443024.7	c.3544A>G	p.Lys1182Glu	missense_variant	32/34	5	NM_002161.6	P1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21749 AN: 152084 Hom.: 1824 Cov.: 32

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.172 AC: 43150 AN: 250814 Hom.: 4162 AF XY: 0.178 AC XY: 24193 AN XY: 135566

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.164 AC: 239049 AN: 1457704 Hom.: 21017 Cov.: 31 AF XY: 0.168 AC XY: 121881 AN XY: 724964

Gnomad4 AFR exome AF: 0.0685

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.143 AC: 21774 AN: 152202 Hom.: 1833 Cov.: 32 AF XY: 0.148 AC XY: 10981 AN XY: 74420

Gnomad4 AFR AF: 0.0736

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.147

Alfa AF: 0.158 Hom.: 5204

Bravo AF: 0.137

TwinsUK AF: 0.146 AC: 541

ALSPAC AF: 0.159 AC: 611

ESP6500AA AF: 0.0729 AC: 321

ESP6500EA AF: 0.162 AC: 1391

ExAC AF: 0.172 AC: 20943

Asia WGS AF: 0.208 AC: 721 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IARS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.39
DEOGEN2	Benign	0.043	T;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.0087	T;T;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.78	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.74	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.033
MPC		0.14
ClinPred		0.0038	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.32

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: rs556155; hg19: chr9-94985637; COSMIC: COSV65116518;