Variant chr1-220143109-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_018060.4(IARS2):c.2726C>T(p.Pro909Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P909S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

IARS2
NM_018060.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.70

Variant links:

Genes affected

IARS2 (HGNC:29685): (isoleucyl-tRNA synthetase 2, mitochondrial) 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. Two forms of isoleucine-tRNA synthetase exist, a cytoplasmic form and a mitochondrial form. This gene encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family. [provided by RefSeq, Dec 2014]

IARS2 links:

IARS2 (HGNC:):

IARS2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-220143108-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 638571.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

PP5

Variant 1-220143109-C-T is Pathogenic according to our data. Variant chr1-220143109-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156553.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-220143109-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IARS2	NM_018060.4 linkuse as main transcript	c.2726C>T	p.Pro909Leu	missense_variant	21/23	ENST00000366922.3	NP_060530.3	Q9NSE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3 linkuse as main transcript	c.2726C>T	p.Pro909Leu	missense_variant	21/23	1	NM_018060.4	ENSP00000355889.2		Q9NSE4
IARS2	ENST00000467924.1 linkuse as main transcript	n.421C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

Peripheral neuropathy;C0086543:Cataract;CN220452:growth hormone deficiency with short stature;CN220453:partial sensorineural deafness

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Samuels research lab, Centre de Recherche du CHU Ste-Justine

Apr 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.82

Sift

Uncertain

0.024

Sift4G

Benign

0.33

Polyphen

0.98

Vest4

0.82

MutPred

0.61

Loss of sheet (P = 0.0126);

MVP

0.52

ClinPred

0.99

GERP RS

5.9

Varity_R

0.19

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over