2-55236741-A-T

Variant names:

• chr2-55236741-A-T
• rs1675843951
• NM_002453.3:c.2091T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002453.3(MTIF2):​c.2091T>A​(p.Asp697Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MTIF2 NM_002453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0887118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002453.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTIF2	NM_002453.3	MANE Select	c.2091T>A	p.Asp697Glu	missense	Exon 16 of 16	NP_002444.2
	MTIF2	NM_001005369.1		c.2091T>A	p.Asp697Glu	missense	Exon 17 of 17	NP_001005369.1	P46199
	MTIF2	NM_001321001.1		c.2091T>A	p.Asp697Glu	missense	Exon 16 of 16	NP_001307930.1	P46199

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTIF2	ENST00000263629.9	TSL:1 MANE Select	c.2091T>A	p.Asp697Glu	missense	Exon 16 of 16	ENSP00000263629.4	P46199
	MTIF2	ENST00000956673.1		c.2139T>A	p.Asp713Glu	missense	Exon 18 of 18	ENSP00000626732.1
	MTIF2	ENST00000918027.1		c.2112T>A	p.Asp704Glu	missense	Exon 17 of 17	ENSP00000588086.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.095
Sift	Benign	0.53	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.34		Loss of loop (P = 0.0804)
MVP		0.66
MPC		0.053
ClinPred		0.27	T
GERP RS		5.9
Varity_R		0.062
gMVP		0.33
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1675843951; hg19: chr2-55463877;