10-133399568-G-A

Position:

• chr10-133399568-G-A

Variant summary

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

The NM_138384.4(MTG1):​c.460G>A​(p.Val154Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 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: 0.0000014 (0 hom.)
• Consequence: MTG1 NM_138384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

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, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTG1	NM_138384.4	c.460G>A	p.Val154Met	missense_variant	6/11	ENST00000317502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTG1	ENST00000317502.11	c.460G>A	p.Val154Met	missense_variant	6/11	1	NM_138384.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 21, 2023

The c.460G>A (p.V154M) alteration is located in exon 6 (coding exon 6) of the MTG1 gene. This alteration results from a G to A substitution at nucleotide position 460, causing the valine (V) at amino acid position 154 to be replaced by a methionine (M). 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	0.91
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	4.5	.;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.81
MutPred		0.83		.;.;Loss of helix (P = 0.028);
MVP		0.75
MPC		0.30
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.37
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1664213380; hg19: chr10-135213072; COSMIC: COSV105889006; COSMIC: COSV105889006;