10-133395773-C-T

Variant names:

• chr10-133395773-C-T
• rs1253195913
• NM_138384.4:c.173C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138384.4(MTG1):​c.173C>T​(p.Ala58Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,618 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: 6.8e-7 (0 hom.)
• Consequence: MTG1 NM_138384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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]

ENSG00000254536 (HGNC:):

ACMG classification

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, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTG1	NM_138384.4	c.173C>T	p.Ala58Val	missense_variant	Exon 2 of 11	ENST00000317502.11	NP_612393.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTG1	ENST00000317502.11	c.173C>T	p.Ala58Val	missense_variant	Exon 2 of 11	1	NM_138384.4	ENSP00000323047.6
MTG1	ENST00000477902.6	c.50C>T	p.Ala17Val	missense_variant	Exon 2 of 11	3		ENSP00000475596.1
ENSG00000254536	ENST00000468317.3	n.*97C>T		non_coding_transcript_exon_variant	Exon 7 of 16	5		ENSP00000436767.2
ENSG00000254536	ENST00000670407.1	n.*339C>T		non_coding_transcript_exon_variant	Exon 6 of 7			ENSP00000499264.1
ENSG00000254536	ENST00000468317.3	n.*97C>T		3_prime_UTR_variant	Exon 7 of 16	5		ENSP00000436767.2
ENSG00000254536	ENST00000670407.1	n.*339C>T		3_prime_UTR_variant	Exon 6 of 7			ENSP00000499264.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727082

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.: 33

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173C>T (p.A58V) alteration is located in exon 2 (coding exon 2) of the MTG1 gene. This alteration results from a C to T substitution at nucleotide position 173, causing the alanine (A) at amino acid position 58 to be replaced by a valine (V). 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	0.84
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	.;.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D;.;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Benign	0.069	T;D;D;D
Polyphen		0.64	.;.;P;.
Vest4		0.82
MutPred		0.87		.;.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.58
MPC		0.15
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.43
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1253195913; hg19: chr10-135209277;