1-220094327-G-C

Position:

• chr1-220094327-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018060.4(IARS2):​c.111G>C​(p.Thr37=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.877

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]

ACMG classification

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/exons	MANE	UniProt
IARS2	NM_018060.4	c.111G>C	p.Thr37=	synonymous_variant	1/23	ENST00000366922.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS2	ENST00000366922.3	c.111G>C	p.Thr37=	synonymous_variant	1/23	1	NM_018060.4	P1

Frequencies

GnomAD3 genomes AF: 0.00884 AC: 1346 AN: 152196 Hom.: 13 Cov.: 32

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.: 17 AF XY: 0.00899 AC XY: 1179 AN XY: 131142

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.: 98 Cov.: 32 AF XY: 0.0101 AC XY: 7304 AN XY: 726596

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.: 13 Cov.: 32 AF XY: 0.00855 AC XY: 637 AN XY: 74480

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.: 5

Bravo AF: 0.00862

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	IARS2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 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. -

IARS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

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

Other links and lift over

dbSNP: rs116823205; hg19: chr1-220267669;