NM_018060.4:c.1640+3476A>G

Variant names:

• chr1-220117950-A-G
• rs72631834
• NM_018060.4:c.1640+3476A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_018060.4(IARS2):​c.1640+3476A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 506,154 control chromosomes in the GnomAD database, including 5 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 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: IARS2 NM_018060.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 2 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]

MIR215 (HGNC:31592): (microRNA 215) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

LOC124904515 (HGNC:):

MIR194-1 (HGNC:31564): (microRNA 194-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00136 (205/150516) while in subpopulation NFE AF = 0.00217 (145/66718). AF 95% confidence interval is 0.00188. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,Unknown gene

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.1640+3476A>G		intron	N/A	NP_060530.3
	MIR215	NR_029628.1		n.13T>C		non_coding_transcript_exon	Exon 1 of 1
	MIR194-1	NR_029711.1		n.*207T>C		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	ENST00000366922.3	TSL:1 MANE Select	c.1640+3476A>G		intron	N/A	ENSP00000355889.2	Q9NSE4
	IARS2	ENST00000930953.1		c.1736+3476A>G		intron	N/A	ENSP00000601012.1
	IARS2	ENST00000948321.1		c.1640+3476A>G		intron	N/A	ENSP00000618380.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 205 AN: 150394 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00477

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00217

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00141 AC: 307 AN: 218112 AF XY: 0.00139

Gnomad AFR exome AF: 0.0000695

Gnomad AMR exome AF: 0.0000645

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00515

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00182 AC: 648 AN: 355638 Hom.: 4 Cov.: 0 AF XY: 0.00178 AC XY: 359 AN XY: 201428

African (AFR) AF: 0.0000981 AC: 1 AN: 10194

American (AMR) AF: 0.0000589 AC: 2 AN: 33978

Ashkenazi Jewish (ASJ) AF: 0.0000901 AC: 1 AN: 11098

East Asian (EAS) AF: 0.00 AC: 0 AN: 13028

South Asian (SAS) AF: 0.000818 AC: 51 AN: 62364

European-Finnish (FIN) AF: 0.00507 AC: 156 AN: 30782

Middle Eastern (MID) AF: 0.000358 AC: 1 AN: 2796

European-Non Finnish (NFE) AF: 0.00237 AC: 416 AN: 175814

Other (OTH) AF: 0.00128 AC: 20 AN: 15584

GnomAD4 genome AF: 0.00136 AC: 205 AN: 150516 Hom.: 1 Cov.: 32 AF XY: 0.00148 AC XY: 109 AN XY: 73684

African (AFR) AF: 0.0000965 AC: 4 AN: 41434

American (AMR) AF: 0.000132 AC: 2 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4796

European-Finnish (FIN) AF: 0.00477 AC: 50 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00217 AC: 145 AN: 66718

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00186 Hom.: 2

Bravo AF: 0.000733

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.82
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism

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: rs72631834; hg19: chr1-220291292;