rs556155

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1833 hom., cov: 32)

Exomes 𝑓: 0.16 ( 21017 hom. )

Consequence

IARS1
NM_002161.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.208

Variant links:

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]

IARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
IARS1	NM_002161.6 link	c.3544A>G	p.Lys1182Glu	missense_variant	Exon 32 of 34	ENST00000443024.7	NP_002152.2	P41252Q6P0M4Q7L4K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS1	ENST00000443024.7 link	c.3544A>G	p.Lys1182Glu	missense_variant	Exon 32 of 34	5	NM_002161.6	ENSP00000406448.4		P41252A0A0A0MSX9

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21749

AN:

152084

Hom.:

1824

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.168

AC XY:

121881

AN XY:

724964

show subpopulations

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.:

AF XY:

0.148

AC XY:

10981

AN XY:

74420

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

IARS1-related disorder

Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.39

DEOGEN2

Benign

0.043

T;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.0087

T;T;T

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

N;.;.

PrimateAI

Benign

0.26

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over