chr1-220094239-G-T

Position:

• chr1-220094239-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.0380

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 -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	UniProt
IARS2	NM_018060.4	c.23G>T	p.Arg8Leu	missense_variant	1/23	ENST00000366922.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2678 AN: 152186 Hom.: 41 Cov.: 32

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

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.: 32 AF XY: 0.0259 AC XY: 18515 AN XY: 715592

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.: 41 Cov.: 32 AF XY: 0.0183 AC XY: 1363 AN XY: 74474

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.: 23

Bravo AF: 0.0151

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00578 AC: 23

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other: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	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.046
ClinPred		0.0050	T
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

Other links and lift over

dbSNP: rs149324758; hg19: chr1-220267581; COSMIC: COSV56959143; COSMIC: COSV56959143;