rs556155

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

35 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=0.0052803755).

BP6

Variant 9-92223355-T-C is Benign according to our data. Variant chr9-92223355-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002161.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IARS1	NM_002161.6	MANE Select	c.3544A>G	p.Lys1182Glu	missense	Exon 32 of 34	NP_002152.2
IARS1	NM_001378569.1		c.3607A>G	p.Lys1203Glu	missense	Exon 32 of 34	NP_001365498.1
IARS1	NM_001378571.1		c.3565A>G	p.Lys1189Glu	missense	Exon 32 of 34	NP_001365500.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IARS1	ENST00000443024.7	TSL:5 MANE Select	c.3544A>G	p.Lys1182Glu	missense	Exon 32 of 34	ENSP00000406448.4
IARS1	ENST00000375643.7	TSL:1	c.3544A>G	p.Lys1182Glu	missense	Exon 32 of 34	ENSP00000364794.3
IARS1	ENST00000447699.7	TSL:1	n.*227A>G		non_coding_transcript_exon	Exon 33 of 35	ENSP00000415020.3

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

GnomAD2 exomes

AF:

0.172

AC:

43150

AN:

250814

AF XY:

0.178

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 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

African (AFR)

AF:

0.0685

AC:

2289

AN:

33436

American (AMR)

AF:

0.191

AC:

8513

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3750

AN:

26042

East Asian (EAS)

AF:

0.107

AC:

4256

AN:

39646

South Asian (SAS)

AF:

0.281

AC:

24087

AN:

85642

European-Finnish (FIN)

AF:

0.178

AC:

9473

AN:

53302

Middle Eastern (MID)

AF:

0.127

AC:

729

AN:

5756

European-Non Finnish (NFE)

AF:

0.159

AC:

176692

AN:

1109170

Other (OTH)

AF:

0.154

AC:

9260

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

8553

17106

25660

34213

42766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6274

12548

18822

25096

31370

<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:

0.143

AC:

21774

AN:

152202

Hom.:

1833

Cov.:

AF XY:

0.148

AC XY:

10981

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0736

AC:

3059

AN:

41536

American (AMR)

AF:

0.184

AC:

2820

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

465

AN:

3472

East Asian (EAS)

AF:

0.104

AC:

539

AN:

5184

South Asian (SAS)

AF:

0.295

AC:

1424

AN:

4824

European-Finnish (FIN)

AF:

0.183

AC:

1939

AN:

10580

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11052

AN:

67994

Other (OTH)

AF:

0.147

AC:

310

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

959

1917

2876

3834

4793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.156

Hom.:

9696

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy (1)

IARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.043

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.0087

MetaRNN

Benign

0.0053

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

PhyloP100

0.21

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.78

REVEL

Benign

0.030

Sift

Benign

0.74

Sift4G

Benign

0.68

Polyphen

0.0

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

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over