NM_018060.4:c.41C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.042 ( 436 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 409 hom. )

Consequence

IARS2
NM_018060.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.29

Publications

4 publications found

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:

BPNT1 (HGNC:1096): (3'(2'), 5'-bisphosphate nucleotidase 1) BPNT1, also called bisphosphate 3-prime-nucleotidase, or BPntase, is a member of a magnesium-dependent phosphomonoesterase family. Lithium, a major drug used to treat manic depression, acts as an uncompetitive inhibitor of BPntase. The predicted human protein is 92% identical to mouse BPntase. BPntase's physiologic role in nucleotide metabolism may be regulated by inositol signaling pathways. The inhibition of human BPntase may account for lithium-induced nephrotoxicity. [provided by RefSeq, Jul 2008]

BPNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	NM_018060.4	MANE Select	c.41C>T	p.Ala14Val	missense	Exon 1 of 23	NP_060530.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IARS2	ENST00000366922.3	TSL:1 MANE Select	c.41C>T	p.Ala14Val	missense	Exon 1 of 23	ENSP00000355889.2	Q9NSE4
IARS2	ENST00000930953.1		c.41C>T	p.Ala14Val	missense	Exon 1 of 23	ENSP00000601012.1
IARS2	ENST00000948321.1		c.41C>T	p.Ala14Val	missense	Exon 1 of 23	ENSP00000618380.1

Frequencies

GnomAD3 genomes

AF:

0.0421

AC:

6402

AN:

152158

Hom.:

435

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0107

AC:

2391

AN:

223178

AF XY:

0.00862

show subpopulations

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 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.:

AF XY:

0.00407

AC XY:

2938

AN XY:

722316

show subpopulations

African (AFR)

AF:

0.149

AC:

4932

AN:

33112

American (AMR)

AF:

0.00812

AC:

357

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

349

AN:

25802

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39454

South Asian (SAS)

AF:

0.000187

AC:

AN:

85538

European-Finnish (FIN)

AF:

0.000309

AC:

AN:

51774

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.000339

AC:

376

AN:

1108294

Other (OTH)

AF:

0.0103

AC:

619

AN:

59858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

342

684

1025

1367

1709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0420

AC:

6397

AN:

152276

Hom.:

436

Cov.:

AF XY:

0.0414

AC XY:

3086

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.144

AC:

5994

AN:

41544

American (AMR)

AF:

0.0161

AC:

246

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68014

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

296

592

889

1185

1481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.0486

ESP6500AA

AF:

0.127

AC:

533

ESP6500EA

AF:

0.000840

AC:

ExAC

AF:

0.0127

AC:

1514

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

IARS2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

1.3

PrimateAI

Uncertain

0.78

Sift4G

Benign

0.067

Polyphen

0.0

Vest4

0.11

ClinPred

0.011

GERP RS

3.2

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.045

gMVP

0.38

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over