9-92268295-G-A

Position:

• chr9-92268295-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002161.6(IARS1):​c.1310C>T​(p.Pro437Leu) 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: 9.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 9-92268295-G-A is Pathogenic according to our data. Variant chr9-92268295-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253319.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-92268295-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IARS1	NM_002161.6	c.1310C>T	p.Pro437Leu	missense_variant	14/34	ENST00000443024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IARS1	ENST00000443024.7	c.1310C>T	p.Pro437Leu	missense_variant	14/34	5	NM_002161.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	5.2	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.8	D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.84		Gain of MoRF binding (P = 0.1086);Gain of MoRF binding (P = 0.1086);.;
MVP		0.93
MPC		0.51
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.99
gMVP		0.94

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: rs886037874; hg19: chr9-95030577; COSMIC: COSV65115634;