9-92242195-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002161.6(IARS1):c.3136G>A(p.Val1046Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0066 in 1,614,020 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 43 hom. )

Consequence

IARS1
NM_002161.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.72

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

IARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070349574).

BP6

Variant 9-92242195-C-T is Benign according to our data. Variant chr9-92242195-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00454 (692/152308) while in subpopulation NFE AF = 0.00807 (549/68016). AF 95% confidence interval is 0.00751. There are 2 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS1	NM_002161.6 link	c.3136G>A	p.Val1046Ile	missense_variant	Exon 29 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.3136G>A	p.Val1046Ile	missense_variant	Exon 29 of 34	5	NM_002161.6	ENSP00000406448.4		P41252A0A0A0MSX9

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

693

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00807

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00468

AC:

1176

AN:

251292

AF XY:

0.00466

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00845

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00681

AC:

9959

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4942

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86244

European-Finnish (FIN)

AF:

0.00247

AC:

132

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00824

AC:

9165

AN:

1111888

Other (OTH)

AF:

0.00548

AC:

331

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

450

900

1349

1799

2249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00454

AC:

692

AN:

152308

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

308

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41566

American (AMR)

AF:

0.00261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00807

AC:

549

AN:

68016

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00672

Hom.:

Bravo

AF:

0.00435

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00502

AC:

610

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00747

EpiControl

AF:

0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IARS1: BP4, BS2 -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 14, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

IARS1-related disorder

Benign:1

Jun 24, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.069

T;.;.;.;.

Eigen

Benign

0.025

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T;T;T;.

M_CAP

Benign

0.025

MetaRNN

Benign

0.0070

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;.;.

PhyloP100

5.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.59

N;.;N;N;N

REVEL

Benign

0.099

Sift

Benign

0.19

T;.;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.31

MVP

0.53

MPC

0.080

ClinPred

0.015

GERP RS

6.0

Varity_R

0.059

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over