1-220117950-A-G

Position:

• chr1-220117950-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

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:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS2	NM_018060.4	c.1640+3476A>G		intron_variant		ENST00000366922.3	NP_060530.3
MIR215	NR_029628.1	n.13T>C		non_coding_transcript_exon_variant	1/1
LOC124904515	XR_007066883.1	n.130-67T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3	c.1640+3476A>G		intron_variant		1	NM_018060.4	ENSP00000355889	P1
MIR215	ENST00000384858.1	n.13T>C		non_coding_transcript_exon_variant	1/1
IARS2	ENST00000490891.1	n.24+3476A>G		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00141 AC: 307 AN: 218112 Hom.: 1 AF XY: 0.00139 AC XY: 163 AN XY: 116870

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 SAS exome AF: 0.000851

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

Gnomad4 AFR exome AF: 0.0000981

Gnomad4 AMR exome AF: 0.0000589

Gnomad4 ASJ exome AF: 0.0000901

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000818

Gnomad4 FIN exome AF: 0.00507

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00128

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

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00477

Gnomad4 NFE AF: 0.00217

Gnomad4 OTH AF: 0.000478

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.82

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: rs72631834; hg19: chr1-220291292;