rs143722284

Positions:

chr1-220137990-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_018060.4(IARS2):c.2122G>A(p.Glu708Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,100 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 7 hom. )

Consequence

IARS2
NM_018060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 9.15

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:

IARS2 (HGNC:):

IARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.092580944).

BP6

Variant 1-220137990-G-A is Benign according to our data. Variant chr1-220137990-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr1-220137990-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00113 (1653/1461838) while in subpopulation SAS AF= 0.00284 (245/86256). AF 95% confidence interval is 0.00255. There are 7 homozygotes in gnomad4_exome. There are 858 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS2	NM_018060.4 linkuse as main transcript	c.2122G>A	p.Glu708Lys	missense_variant	17/23	ENST00000366922.3	NP_060530.3	Q9NSE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3 linkuse as main transcript	c.2122G>A	p.Glu708Lys	missense_variant	17/23	1	NM_018060.4	ENSP00000355889.2		Q9NSE4
IARS2	ENST00000488777.1 linkuse as main transcript	n.349G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00127

AC:

319

AN:

251460

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00300

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00113

AC:

1653

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

858

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00284

Gnomad4 FIN exome

AF:

0.00354

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000933

AC:

142

AN:

152262

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	IARS2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30419932, 30041933, 25130867, 34426522, LopesBragaV2023[article], 33972171, 39062673) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Leigh syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Samuels research lab, Centre de Recherche du CHU Ste-Justine

Apr 01, 2014

- -

Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 12, 2024

Variant summary: IARS2 c.2122G>A (p.Glu708Lys) results in a conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 251460 control chromosomes, predominantly at a frequency of 0.003 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in IARS2 causing Cataract-Growth Hormone Deficiency-Sensory Neuropathy-Sensorineural Hearing Loss-Skeletal Dysplasia Syndrome phenotype. c.2122G>A has been reported in the literature in the presumed compound heterozygous state in multiple individuals affected with clinical features of IARS2-related conditions, however the the population frequency of this variant is not in pathogenic range. These report(s) do not provide unequivocal conclusions about association of the variant with IARS2-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33327715, 33972171, 25130867). ClinVar contains an entry for this variant (Variation ID: 156552). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.0

PrimateAI

Uncertain

0.63

REVEL

Uncertain

0.43

Sift4G

Benign

0.13

Polyphen

0.94

Vest4

0.94

MVP

0.61

ClinPred

0.11

GERP RS

6.0

Varity_R

0.62

gMVP

0.69

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