rs886037877

Positions:

• chr9-92243242-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002161.6(IARS1):​c.2974A>G​(p.Asn992Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IARS1 NM_002161.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.62

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 9-92243242-T-C is Pathogenic according to our data. Variant chr9-92243242-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 253322.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-92243242-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS1	NM_002161.6	c.2974A>G	p.Asn992Asp	missense_variant	28/34	ENST00000443024.7	NP_002152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IARS1	ENST00000443024.7	c.2974A>G	p.Asn992Asp	missense_variant	28/34	5	NM_002161.6	ENSP00000406448.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D;.;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.46	P;.;.;.;.
Vest4		0.93
MutPred		0.71		Loss of MoRF binding (P = 0.0608);.;Loss of MoRF binding (P = 0.0608);.;.;
MVP		0.73
MPC		0.31
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs886037877; hg19: chr9-95005524;