rs116823205

Variant names:

• chr1-220094327-G-C
• rs116823205
• NM_018060.4:c.111G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018060.4(IARS2):​c.111G>C​(p.Thr37Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,858 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (13 hom., cov: 32)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: IARS2 NM_018060.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.877
• 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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-220094327-G-C is Benign according to our data. Variant chr1-220094327-G-C is described in ClinVar as Benign. ClinVar VariationId is 381167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.877 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00884 (1347/152314) while in subpopulation NFE AF = 0.0123 (838/68004). AF 95% confidence interval is 0.0116. There are 13 homozygotes in GnomAd4. There are 637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.111G>C	p.Thr37Thr	synonymous	Exon 1 of 23	NP_060530.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	ENST00000366922.3	TSL:1 MANE Select	c.111G>C	p.Thr37Thr	synonymous	Exon 1 of 23	ENSP00000355889.2	Q9NSE4
	IARS2	ENST00000930953.1		c.111G>C	p.Thr37Thr	synonymous	Exon 1 of 23	ENSP00000601012.1
	IARS2	ENST00000948321.1		c.111G>C	p.Thr37Thr	synonymous	Exon 1 of 23	ENSP00000618380.1

Frequencies

GnomAD3 genomes AF: 0.00884 AC: 1346 AN: 152196 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00892 AC: 2140 AN: 239802 AF XY: 0.00899

Gnomad AFR exome AF: 0.00180

Gnomad AMR exome AF: 0.00812

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0103 AC: 15057 AN: 1460544 Hom.: 98 Cov.: 32 AF XY: 0.0101 AC XY: 7304 AN XY: 726596

African (AFR) AF: 0.00180 AC: 60 AN: 33402

American (AMR) AF: 0.00862 AC: 385 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 416 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86216

European-Finnish (FIN) AF: 0.00913 AC: 483 AN: 52882

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.0118 AC: 13080 AN: 1111552

Other (OTH) AF: 0.00872 AC: 526 AN: 60296

GnomAD4 genome AF: 0.00884 AC: 1347 AN: 152314 Hom.: 13 Cov.: 32 AF XY: 0.00855 AC XY: 637 AN XY: 74480

African (AFR) AF: 0.00226 AC: 94 AN: 41582

American (AMR) AF: 0.0106 AC: 163 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10624

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0123 AC: 838 AN: 68004

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0112 Hom.: 5

Bravo AF: 0.00862

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0141

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	IARS2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.65
PhyloP100		-0.88
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs116823205; hg19: chr1-220267669;