rs3820455

Variant names:

• chr1-220118145-T-C
• rs3820455
• NM_018060.4:c.1640+3671T>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+3671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 494,928 control chromosomes in the GnomAD database, including 702 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 0.051 (245 hom., cov: 32)
  • Exomes 𝑓: 0.043 (457 hom.)
• Consequence: IARS2 NM_018060.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 9 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]

LOC124904515 (HGNC:):

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]

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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS2	NM_018060.4	c.1640+3671T>C		intron_variant	Intron 12 of 22	ENST00000366922.3	NP_060530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3	c.1640+3671T>C		intron_variant	Intron 12 of 22	1	NM_018060.4	ENSP00000355889.2
IARS2	ENST00000490891.1	n.24+3671T>C		intron_variant	Intron 1 of 5	3
MIR215	ENST00000384858.1	n.-183A>G		upstream_gene_variant		6
MIR194-1	ENST00000384892.1	n.*12A>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7772 AN: 152188 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0983

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0526

GnomAD2 exomes AF: 0.0484 AC: 9608 AN: 198598 AF XY: 0.0479

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0431

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0433 AC: 14820 AN: 342622 Hom.: 457 Cov.: 0 AF XY: 0.0431 AC XY: 8372 AN XY: 194316

African (AFR) AF: 0.0747 AC: 710 AN: 9500

American (AMR) AF: 0.0295 AC: 938 AN: 31756

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 967 AN: 11000

East Asian (EAS) AF: 0.129 AC: 1580 AN: 12218

South Asian (SAS) AF: 0.0389 AC: 2371 AN: 60950

European-Finnish (FIN) AF: 0.0135 AC: 404 AN: 29818

Middle Eastern (MID) AF: 0.0541 AC: 134 AN: 2478

European-Non Finnish (NFE) AF: 0.0410 AC: 6971 AN: 169916

Other (OTH) AF: 0.0497 AC: 745 AN: 14986

GnomAD4 genome AF: 0.0512 AC: 7805 AN: 152306 Hom.: 245 Cov.: 32 AF XY: 0.0501 AC XY: 3734 AN XY: 74478

African (AFR) AF: 0.0723 AC: 3006 AN: 41574

American (AMR) AF: 0.0420 AC: 643 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 341 AN: 3468

East Asian (EAS) AF: 0.110 AC: 572 AN: 5180

South Asian (SAS) AF: 0.0424 AC: 205 AN: 4830

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10622

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2778 AN: 68008

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0453 Hom.: 489

Bravo AF: 0.0548

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.1
DANN	Benign	0.86
PhyloP100		-0.33
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: rs3820455; hg19: chr1-220291487;