chr1-220094257-C-T

Position:

• chr1-220094257-C-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.41C>T​(p.Ala14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,605,590 control chromosomes in the GnomAD database, including 845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.042 (436 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (409 hom.)
• Consequence: IARS2 NM_018060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.29

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=0.0015183985).
• BP6: Variant 1-220094257-C-T is Benign according to our data. Variant chr1-220094257-C-T is described in ClinVar as [Benign]. Clinvar id is 381429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS2	NM_018060.4	c.41C>T	p.Ala14Val	missense_variant	1/23	ENST00000366922.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS2	ENST00000366922.3	c.41C>T	p.Ala14Val	missense_variant	1/23	1	NM_018060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6402 AN: 152158 Hom.: 435 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0107 AC: 2391 AN: 223178 Hom.: 153 AF XY: 0.00862 AC XY: 1064 AN XY: 123474

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.000100

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.00549

GnomAD4 exome AF: 0.00463 AC: 6727 AN: 1453314 Hom.: 409 Cov.: 32 AF XY: 0.00407 AC XY: 2938 AN XY: 722316

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.000309

Gnomad4 NFE exome AF: 0.000339

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0420 AC: 6397 AN: 152276 Hom.: 436 Cov.: 32 AF XY: 0.0414 AC XY: 3086 AN XY: 74460

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0143 Hom.: 28

Bravo AF: 0.0486

ESP6500AA AF: 0.127 AC: 533

ESP6500EA AF: 0.000840 AC: 7

ExAC AF: 0.0127 AC: 1514

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 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 09, 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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.067	T
Polyphen		0.0	B
Vest4		0.11
ClinPred		0.011	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.045
gMVP		0.38

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: rs2577154; hg19: chr1-220267599;