chr1-220126693-T-C

Variant names:

• chr1-220126693-T-C
• rs2289191
• NM_018060.4:c.1744-57T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018060.4(IARS2):​c.1744-57T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0699 in 1,244,492 control chromosomes in the GnomAD database, including 3,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (309 hom., cov: 32)
  • Exomes 𝑓: 0.072 (3111 hom.)
• Consequence: IARS2 NM_018060.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.160
• Publications: 8 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]

IARS2 Gene-Disease associations (from GenCC):

• cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

  Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-220126693-T-C is Benign according to our data. Variant chr1-220126693-T-C is described in ClinVar as Benign. ClinVar VariationId is 676218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0736 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	NM_018060.4	MANE Select	c.1744-57T>C		intron	N/A	NP_060530.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS2	ENST00000366922.3	TSL:1 MANE Select	c.1744-57T>C		intron	N/A	ENSP00000355889.2	Q9NSE4
	IARS2	ENST00000930953.1		c.1840-57T>C		intron	N/A	ENSP00000601012.1
	IARS2	ENST00000948321.1		c.1744-57T>C		intron	N/A	ENSP00000618380.1

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8176 AN: 152138 Hom.: 307 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0613

GnomAD4 exome AF: 0.0722 AC: 78847 AN: 1092236 Hom.: 3111 AF XY: 0.0725 AC XY: 40569 AN XY: 559914

African (AFR) AF: 0.0107 AC: 274 AN: 25568

American (AMR) AF: 0.0367 AC: 1408 AN: 38378

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2446 AN: 23482

East Asian (EAS) AF: 0.0428 AC: 1612 AN: 37704

South Asian (SAS) AF: 0.0632 AC: 4728 AN: 74856

European-Finnish (FIN) AF: 0.0676 AC: 3592 AN: 53142

Middle Eastern (MID) AF: 0.0711 AC: 359 AN: 5052

European-Non Finnish (NFE) AF: 0.0777 AC: 61042 AN: 785790

Other (OTH) AF: 0.0702 AC: 3386 AN: 48264

GnomAD4 genome AF: 0.0537 AC: 8177 AN: 152256 Hom.: 309 Cov.: 32 AF XY: 0.0530 AC XY: 3942 AN XY: 74442

African (AFR) AF: 0.0131 AC: 545 AN: 41560

American (AMR) AF: 0.0457 AC: 699 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5176

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4820

European-Finnish (FIN) AF: 0.0662 AC: 703 AN: 10612

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0753 AC: 5125 AN: 68016

Other (OTH) AF: 0.0611 AC: 129 AN: 2110

Alfa AF: 0.0710 Hom.: 719

Bravo AF: 0.0499

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.82
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2289191;

hg19: chr1-220300035;

COSMIC: COSV56963881;