rs4743869

Variant names:

• chr9-92247934-T-C
• rs4743869
• NM_002161.6:c.2617-383A>G

Variant summary

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

The NM_002161.6(IARS1):​c.2617-383A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,160 control chromosomes in the GnomAD database, including 28,397 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 0.58 (28397 hom., cov: 33)
• Consequence: IARS1 NM_002161.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 3 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, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002161.6. 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
	IARS1	NM_002161.6	MANE Select	c.2617-383A>G		intron	N/A	NP_002152.2	P41252
	IARS1	NM_001378569.1		c.2680-383A>G		intron	N/A	NP_001365498.1
	IARS1	NM_001378571.1		c.2638-383A>G		intron	N/A	NP_001365500.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IARS1	ENST00000443024.7	TSL:5 MANE Select	c.2617-383A>G		intron	N/A	ENSP00000406448.4	P41252
	IARS1	ENST00000375643.7	TSL:1	c.2617-383A>G		intron	N/A	ENSP00000364794.3	P41252
	IARS1	ENST00000447699.7	TSL:1	n.2617-383A>G		intron	N/A	ENSP00000415020.3	J3KR24

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88631 AN: 152042 Hom.: 28343 Cov.: 33

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.558

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.583 AC: 88735 AN: 152160 Hom.: 28397 Cov.: 33 AF XY: 0.578 AC XY: 42965 AN XY: 74386

African (AFR) AF: 0.857 AC: 35603 AN: 41538

American (AMR) AF: 0.488 AC: 7472 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1790 AN: 3468

East Asian (EAS) AF: 0.213 AC: 1107 AN: 5188

South Asian (SAS) AF: 0.517 AC: 2493 AN: 4818

European-Finnish (FIN) AF: 0.461 AC: 4875 AN: 10566

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33409 AN: 67960

Other (OTH) AF: 0.552 AC: 1169 AN: 2116

Alfa AF: 0.523 Hom.: 10326

Bravo AF: 0.595

Asia WGS AF: 0.399 AC: 1387 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.19
DANN	Benign	0.53
PhyloP100		-1.8
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: rs4743869; hg19: chr9-95010216;