Genetic Variant IARS2:p.Trp607Cys (chr1-220126827-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018060.4(IARS2):c.1821G>T(p.Trp607Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IARS2
NM_018060.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.35

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

IARS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS2	NM_018060.4 link	c.1821G>T	p.Trp607Cys	missense_variant	Exon 14 of 23	ENST00000366922.3	NP_060530.3	Q9NSE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3 link	c.1821G>T	p.Trp607Cys	missense_variant	Exon 14 of 23	1	NM_018060.4	ENSP00000355889.2		Q9NSE4
IARS2	ENST00000490891.1 link	n.205G>T		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456994

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33230

American (AMR)

AF:

0.00

AC:

AN:

43302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

84976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110362

Other (OTH)

AF:

0.00

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.043

MutationAssessor

Pathogenic

3.8

PhyloP100

8.4

PrimateAI

Uncertain

0.75

REVEL

Uncertain

0.59

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.65

Gain of helix (P = 0.1736);

MVP

0.62

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.89

Mutation Taster

=14/86

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over