10-133394279-T-G

Position:

• chr10-133394279-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138384.4(MTG1):​c.59T>G​(p.Phe20Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000293 in 1,364,710 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: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MTG1 NM_138384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

Genes affected

MTG1 (HGNC:32159): (mitochondrial ribosome associated GTPase 1) Enables GTPase activity. Involved in regulation of mitochondrial translation and regulation of respiratory system process. Located in mitochondrial inner membrane and mitochondrial ribosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTG1	NM_138384.4	c.59T>G	p.Phe20Cys	missense_variant	1/11	ENST00000317502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTG1	ENST00000317502.11	c.59T>G	p.Phe20Cys	missense_variant	1/11	1	NM_138384.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1364710 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 673242

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: 0.00000374

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

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

Dec 01, 2022

The c.59T>G (p.F20C) alteration is located in exon 1 (coding exon 1) of the MTG1 gene. This alteration results from a T to G substitution at nucleotide position 59, causing the phenylalanine (F) at amino acid position 20 to be replaced by a cysteine (C). 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	0.86
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.035	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.69		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.65
MPC		0.19
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.20
gMVP		0.74

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: rs1849745980; hg19: chr10-135207783;