rs1058751

Variant names:

• chr9-92210634-T-A
• rs1058751
• ENST00000447699.7:n.*645A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000447699.7(IARS1):​n.*645A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 560,654 control chromosomes in the GnomAD database, including 4,894 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 0.11 (1104 hom., cov: 33)
  • Exomes 𝑓: 0.13 (3790 hom.)
• Consequence: IARS1 ENST00000447699.7 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• Publications: 9 publications found

Genes affected

IARS1 (HGNC:5330): (isoleucyl-tRNA synthetase 1) 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. Isoleucine-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family and has been identified as a target of autoantibodies in the autoimmune disease polymyositis/dermatomyositis. Alternatively spliced transcript variants have been found. [provided by RefSeq, Nov 2012]

IARS1 Gene-Disease associations (from GenCC):

• growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS1	NM_002161.6	c.*173A>T		3_prime_UTR_variant	Exon 34 of 34	ENST00000443024.7	NP_002152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS1	ENST00000443024.7	c.*173A>T		3_prime_UTR_variant	Exon 34 of 34	5	NM_002161.6	ENSP00000406448.4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17084 AN: 152120 Hom.: 1100 Cov.: 33

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.0652

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.127 AC: 51900 AN: 408416 Hom.: 3790 Cov.: 3 AF XY: 0.132 AC XY: 28099 AN XY: 213442

African (AFR) AF: 0.0638 AC: 748 AN: 11724

American (AMR) AF: 0.166 AC: 2856 AN: 17198

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 1018 AN: 12432

East Asian (EAS) AF: 0.0564 AC: 1654 AN: 29314

South Asian (SAS) AF: 0.214 AC: 7527 AN: 35250

European-Finnish (FIN) AF: 0.157 AC: 5923 AN: 37794

Middle Eastern (MID) AF: 0.110 AC: 365 AN: 3316

European-Non Finnish (NFE) AF: 0.122 AC: 29082 AN: 237968

Other (OTH) AF: 0.116 AC: 2727 AN: 23420

GnomAD4 genome AF: 0.112 AC: 17102 AN: 152238 Hom.: 1104 Cov.: 33 AF XY: 0.117 AC XY: 8740 AN XY: 74422

African (AFR) AF: 0.0667 AC: 2770 AN: 41542

American (AMR) AF: 0.156 AC: 2388 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 269 AN: 3468

East Asian (EAS) AF: 0.0653 AC: 339 AN: 5188

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4826

European-Finnish (FIN) AF: 0.164 AC: 1735 AN: 10584

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8243 AN: 68022

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.119 Hom.: 148

Bravo AF: 0.108

Asia WGS AF: 0.122 AC: 423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.58
PhyloP100		-0.022
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

Other links and lift over

dbSNP: rs1058751; hg19: chr9-94972916; COSMIC: COSV65116796; COSMIC: COSV65116796;