13-27435845-A-G

Variant summary

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

The NM_152912.5(MTIF3):c.667T>C(p.Phe223Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTIF3 NM_152912.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32

Genes affected

MTIF3 (HGNC:29788): (mitochondrial translational initiation factor 3) This gene encodes a translation initiation factor that is involved in mitochondrial protein synthesis. Polymorphism in this gene is associated with the onset of Parkinson's disease. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 5. [provided by RefSeq, Oct 2009]

GTF3A (HGNC:4662): (general transcription factor IIIA) The product of this gene is a zinc finger protein with nine Cis[2]-His[2] zinc finger domains. It functions as an RNA polymerase III transcription factor to induce transcription of the 5S rRNA genes. The protein binds to a 50 bp internal promoter in the 5S genes called the internal control region (ICR), and nucleates formation of a stable preinitiation complex. This complex recruits the TFIIIC and TFIIIB transcription factors and RNA polymerase III to form the complete transcription complex. The protein is thought to be translated using a non-AUG translation initiation site in mammals based on sequence analysis, protein homology, and the size of the purified protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTIF3	NM_152912.5	c.667T>C	p.Phe223Leu	missense_variant	5/5	ENST00000381120.8
GTF3A	NM_002097.3			downstream_gene_variant		ENST00000381140.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTIF3	ENST00000381120.8	c.667T>C	p.Phe223Leu	missense_variant	5/5	1	NM_152912.5	P1
GTF3A	ENST00000381140.10			downstream_gene_variant		1	NM_002097.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.667T>C (p.F223L) alteration is located in exon 6 (coding exon 3) of the MTIF3 gene. This alteration results from a T to C substitution at nucleotide position 667, causing the phenylalanine (F) at amino acid position 223 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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.42	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.055	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.38
MutPred		0.44		Gain of catalytic residue at S224 (P = 0.0015);Gain of catalytic residue at S224 (P = 0.0015);Gain of catalytic residue at S224 (P = 0.0015);
MVP		0.54
MPC		0.68
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.42

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: rs1953720023; hg19: chr13-28009982;