1-220115616-A-C

Variant names:

• chr1-220115616-A-C
• rs17007135
• NM_018060.4:c.1640+1142A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018060.4(IARS2):​c.1640+1142A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,100 control chromosomes in the GnomAD database, including 1,506 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1506 hom., cov: 33)
• Consequence: IARS2 NM_018060.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.939
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	NM_018060.4	MANE Select	c.1640+1142A>C		intron	N/A	NP_060530.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	ENST00000366922.3	TSL:1 MANE Select	c.1640+1142A>C		intron	N/A	ENSP00000355889.2
	IARS2	ENST00000930953.1		c.1736+1142A>C		intron	N/A	ENSP00000601012.1
	IARS2	ENST00000948321.1		c.1640+1142A>C		intron	N/A	ENSP00000618380.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19726 AN: 151982 Hom.: 1495 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0856

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.130

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.130 AC: 19774 AN: 152100 Hom.: 1506 Cov.: 33 AF XY: 0.129 AC XY: 9558 AN XY: 74370

African (AFR) AF: 0.111 AC: 4614 AN: 41520

American (AMR) AF: 0.104 AC: 1584 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 848 AN: 3466

East Asian (EAS) AF: 0.171 AC: 885 AN: 5174

South Asian (SAS) AF: 0.196 AC: 944 AN: 4814

European-Finnish (FIN) AF: 0.0856 AC: 908 AN: 10602

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9565 AN: 67940

Other (OTH) AF: 0.132 AC: 280 AN: 2114

Alfa AF: 0.138 Hom.: 524

Bravo AF: 0.128

Asia WGS AF: 0.164 AC: 569 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17007135; hg19: chr1-220288958;