9-92210883-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_002161.6(IARS1):c.3713C>T(p.Thr1238Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000182 in 1,598,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

IARS1
NM_002161.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.81

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 -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0075376034).

BP6

Variant 9-92210883-G-A is Benign according to our data. Variant chr9-92210883-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 744089.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00102 (155/152180) while in subpopulation AFR AF= 0.00344 (143/41536). AF 95% confidence interval is 0.00298. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS1	NM_002161.6 linkuse as main transcript	c.3713C>T	p.Thr1238Ile	missense_variant	34/34	ENST00000443024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS1	ENST00000443024.7 linkuse as main transcript	c.3713C>T	p.Thr1238Ile	missense_variant	34/34	5	NM_002161.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251244

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000940

AC:

136

AN:

1446272

Hom.:

Cov.:

AF XY:

0.0000777

AC XY:

AN XY:

720526

show subpopulations

Gnomad4 AFR exome

AF:

0.00362

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

152180

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000994

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.067

T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.092

Sift

Benign

0.054

T;T;D

Sift4G

Benign

0.061

T;T;T

Polyphen

0.22

B;.;.

Vest4

0.49

MVP

0.49

MPC

0.16

ClinPred

0.035

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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