1-220094353-C-G

Variant names:

• chr1-220094353-C-G
• rs772530946
• NM_018060.4:c.137C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018060.4(IARS2):​c.137C>G​(p.Ser46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IARS2 NM_018060.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12337607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IARS2	NM_018060.4	c.137C>G	p.Ser46Cys	missense_variant	Exon 1 of 23	ENST00000366922.3	NP_060530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IARS2	ENST00000366922.3	c.137C>G	p.Ser46Cys	missense_variant	Exon 1 of 23	1	NM_018060.4	ENSP00000355889.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.21	B
Vest4		0.14
MutPred		0.41		Loss of glycosylation at S46 (P = 0.0061);
MVP		0.52
ClinPred		0.79	D
GERP RS		3.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.18
gMVP		0.31

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: rs772530946; hg19: chr1-220267695;