1-220094239-G-T

Position:

chr1-220094239-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018060.4(IARS2):c.23G>T(p.Arg8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,593,820 control chromosomes in the GnomAD database, including 735 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 32)

Exomes 𝑓: 0.024 ( 694 hom. )

Consequence

IARS2
NM_018060.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.0380

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015715361).

BP6

Variant 1-220094239-G-T is Benign according to our data. Variant chr1-220094239-G-T is described in ClinVar as [Benign]. Clinvar id is 380570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS2	NM_018060.4 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/23	ENST00000366922.3	NP_060530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/23	1	NM_018060.4	ENSP00000355889	P1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2678

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0134

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.0183

Gnomad SAS

AF:

0.0945

Gnomad FIN

AF:

0.00697

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0220

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0281

AC:

5950

AN:

211996

Hom.:

166

AF XY:

0.0322

AC XY:

3789

AN XY:

117700

show subpopulations

Gnomad AFR exome

AF:

0.00404

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0393

Gnomad EAS exome

AF:

0.0173

Gnomad SAS exome

AF:

0.0917

Gnomad FIN exome

AF:

0.00811

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0233

GnomAD4 exome

AF:

0.0237

AC:

34215

AN:

1441518

Hom.:

694

Cov.:

AF XY:

0.0259

AC XY:

18515

AN XY:

715592

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.0407

Gnomad4 EAS exome

AF:

0.0288

Gnomad4 SAS exome

AF:

0.0900

Gnomad4 FIN exome

AF:

0.00813

Gnomad4 NFE exome

AF:

0.0197

Gnomad4 OTH exome

AF:

0.0254

GnomAD4 genome

AF:

0.0176

AC:

2677

AN:

152302

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1363

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0395

Gnomad4 EAS

AF:

0.0184

Gnomad4 SAS

AF:

0.0944

Gnomad4 FIN

AF:

0.00697

Gnomad4 NFE

AF:

0.0220

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.0236

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00578

AC:

ESP6500EA

AF:

0.0192

AC:

155

ExAC

AF:

0.0260

AC:

3052

Asia WGS

AF:

0.0580

AC:

202

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.015

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.75

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.046

ClinPred

0.0050

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.066

gMVP

0.37

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