2-55244150-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002453.3(MTIF2):c.1190G>A(p.Arg397His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,816 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
MTIF2
NM_002453.3 missense
NM_002453.3 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 7.71
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]
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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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTIF2 | NM_002453.3 | c.1190G>A | p.Arg397His | missense_variant | 11/16 | ENST00000263629.9 | NP_002444.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MTIF2 | ENST00000263629.9 | c.1190G>A | p.Arg397His | missense_variant | 11/16 | 1 | NM_002453.3 | ENSP00000263629 | P1 | |
MTIF2 | ENST00000394600.7 | c.1190G>A | p.Arg397His | missense_variant | 8/13 | 2 | ENSP00000378099 | P1 | ||
MTIF2 | ENST00000403721.5 | c.1190G>A | p.Arg397His | missense_variant | 10/15 | 5 | ENSP00000384481 | P1 | ||
MTIF2 | ENST00000418823.4 | c.344+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | ENSP00000403492 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251398Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727208
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2022 | The c.1190G>A (p.R397H) alteration is located in exon 12 (coding exon 8) of the MTIF2 gene. This alteration results from a G to A substitution at nucleotide position 1190, causing the arginine (R) at amino acid position 397 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);
MVP
MPC
0.39
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at