chr9-92268294-TGG-CAA

Variant names:

• chr9-92268294-TGG-CAA
• NM_002161.6:c.1309_1311delCCAinsTTG
• IARS1 p.Pro437Leu

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_002161.6(IARS1):​c.1309_1311delCCAinsTTG​(p.Pro437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IARS1 NM_002161.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.87
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_002161.6 (IARS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1309_1311delCCAinsTTG	p.Pro437Leu	missense	N/A	NP_002152.2	P41252
	IARS1	NM_001378569.1		c.1372_1374delCCAinsTTG	p.Pro458Leu	missense	N/A	NP_001365498.1
	IARS1	NM_001378571.1		c.1330_1332delCCAinsTTG	p.Pro444Leu	missense	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.1309_1311delCCAinsTTG	p.Pro437Leu	missense	N/A	ENSP00000406448.4	P41252
	IARS1	ENST00000375643.7	TSL:1	c.1309_1311delCCAinsTTG	p.Pro437Leu	missense	N/A	ENSP00000364794.3	P41252
	IARS1	ENST00000447699.7	TSL:1	n.1309_1311delCCAinsTTG		non_coding_transcript_exon	Exon 14 of 35	ENSP00000415020.3	J3KR24

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

hg19: chr9-95030576;