9-92222663-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_002161.6(IARS1):c.3563T>C(p.Met1188Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000469 in 1,614,004 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00047 ( 2 hom. )

Consequence

IARS1
NM_002161.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.45

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0145692825).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000427 (65/152210) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS1	NM_002161.6 linkuse as main transcript	c.3563T>C	p.Met1188Thr	missense_variant	33/34	ENST00000443024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS1	ENST00000443024.7 linkuse as main transcript	c.3563T>C	p.Met1188Thr	missense_variant	33/34	5	NM_002161.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

251332

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000473

AC:

692

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

363

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000427

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000693

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

The c.3563T>C (p.M1188T) alteration is located in exon 33 (coding exon 32) of the IARS gene. This alteration results from a T to C substitution at nucleotide position 3563, causing the methionine (M) at amino acid position 1188 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1188 of the IARS protein (p.Met1188Thr). This variant is present in population databases (rs201071417, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with IARS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with growth retardation, impaired intellectual development, hypotonia, and hepatopathy (MIM#617093). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (130 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0806 - This variant has limited previous evidence of being benign in unrelated individuals. The variant has previously been observed in a patient, however it was discounted due to high population frequency, lack of conservation and an alternative genetic cause was identified (PMID: 24706940). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.57

Cadd

Benign

Dann

Benign

0.58

DEOGEN2

Benign

0.041

T;.;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.59

T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.81

N;.;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.024

Sift

Benign

0.67

T;T;T

Sift4G

Benign

0.82

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.23

MVP

0.23

MPC

0.11

ClinPred

0.0011

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.24

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