chr1-220094295-C-T

Position:

• chr1-220094295-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018060.4(IARS2):​c.79C>T​(p.Leu27Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: IARS2 NM_018060.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.157

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046914905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS2	NM_018060.4	c.79C>T	p.Leu27Phe	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	c.79C>T	p.Leu27Phe	missense_variant	1/23	1	NM_018060.4	ENSP00000355889	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000424 AC: 1 AN: 235660 Hom.: 0 AF XY: 0.00000772 AC XY: 1 AN XY: 129572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459504 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.79C>T (p.L27F) alteration is located in exon 1 (coding exon 1) of the IARS2 gene. This alteration results from a C to T substitution at nucleotide position 79, causing the leucine (L) at amino acid position 27 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with IARS2-related conditions. This variant is present in population databases (rs752456634, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 27 of the IARS2 protein (p.Leu27Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.4
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.18		Loss of loop (P = 0.0128);
MVP		0.20
ClinPred		0.031	T
GERP RS		-2.1
Varity_R		0.052
gMVP		0.18

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: rs752456634; hg19: chr1-220267637;