2-55243502-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002453.3(MTIF2):c.1478G>T(p.Arg493Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R493Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MTIF2
NM_002453.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

MTIF2 (HGNC:7441): (mitochondrial translational initiation factor 2) During the initiation of protein biosynthesis, initiation factor-2 (IF-2) promotes the binding of the initiator tRNA to the small subunit of the ribosome in a GTP-dependent manner. Prokaryotic IF-2 is a single polypeptide, while eukaryotic cytoplasmic IF-2 (eIF-2) is a trimeric protein. Bovine liver mitochondria contain IF-2(mt), an 85-kD monomeric protein that is equivalent to prokaryotic IF-2. The predicted 727-amino acid human protein contains a 29-amino acid presequence. Human IF-2(mt) shares 32 to 38% amino acid sequence identity with yeast IF-2(mt) and several prokaryotic IF-2s, with the greatest degree of conservation in the G domains of the proteins. [provided by RefSeq, Mar 2016]

MTIF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06969118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTIF2	NM_002453.3 link	c.1478G>T	p.Arg493Leu	missense_variant	Exon 12 of 16	ENST00000263629.9	NP_002444.2	P46199Q6P1N2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTIF2	ENST00000263629.9 link	c.1478G>T	p.Arg493Leu	missense_variant	Exon 12 of 16	1	NM_002453.3	ENSP00000263629.4	P46199
MTIF2	ENST00000394600.7 link	c.1478G>T	p.Arg493Leu	missense_variant	Exon 9 of 13	2		ENSP00000378099.3	P46199
MTIF2	ENST00000403721.5 link	c.1478G>T	p.Arg493Leu	missense_variant	Exon 11 of 15	5		ENSP00000384481.1	P46199
MTIF2	ENST00000418823.4 link	c.509G>T	p.Arg170Leu	missense_variant	Exon 4 of 6	5		ENSP00000403492.4	H7C213

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251388

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

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:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1478G>T (p.R493L) alteration is located in exon 13 (coding exon 9) of the MTIF2 gene. This alteration results from a G to T substitution at nucleotide position 1478, causing the arginine (R) at amino acid position 493 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.33

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.42

.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.070

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.81

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.68

N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.17

MVP

0.30

MPC

0.065

ClinPred

0.026

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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