NM_018060.4:c.111G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018060.4(IARS2):c.111G>C(p.Thr37Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,858 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 13 hom., cov: 32)

Exomes 𝑓: 0.010 ( 98 hom. )

Consequence

IARS2
NM_018060.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.877

Variant links:

Genes affected

IARS2 (HGNC:29685): (isoleucyl-tRNA synthetase 2, mitochondrial) 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. Two forms of isoleucine-tRNA synthetase exist, a cytoplasmic form and a mitochondrial form. This gene encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family. [provided by RefSeq, Dec 2014]

IARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 1-220094327-G-C is Benign according to our data. Variant chr1-220094327-G-C is described in ClinVar as [Benign]. Clinvar id is 381167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.877 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00884 (1347/152314) while in subpopulation NFE AF= 0.0123 (838/68004). AF 95% confidence interval is 0.0116. There are 13 homozygotes in gnomad4. There are 637 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS2	NM_018060.4 link	c.111G>C	p.Thr37Thr	synonymous_variant	Exon 1 of 23	ENST00000366922.3	NP_060530.3	Q9NSE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3 link	c.111G>C	p.Thr37Thr	synonymous_variant	Exon 1 of 23	1	NM_018060.4	ENSP00000355889.2		Q9NSE4

Frequencies

GnomAD3 genomes

AF:

0.00884

AC:

1346

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00892

AC:

2140

AN:

239802

Hom.:

AF XY:

0.00899

AC XY:

1179

AN XY:

131142

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.00812

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000723

Gnomad FIN exome

AF:

0.00952

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0103

AC:

15057

AN:

1460544

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7304

AN XY:

726596

show subpopulations

Gnomad4 AFR exome

AF:

0.00180

Gnomad4 AMR exome

AF:

0.00862

Gnomad4 ASJ exome

AF:

0.0159

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.00913

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.00872

GnomAD4 genome

AF:

0.00884

AC:

1347

AN:

152314

Hom.:

Cov.:

AF XY:

0.00855

AC XY:

637

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00226

Gnomad4 AMR

AF:

0.0106

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0123

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.00862

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IARS2: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

IARS2-related disorder

Benign:1

Jan 20, 2020

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.3

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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