10-133399542-G-A

Variant names:

• chr10-133399542-G-A
• rs146230872
• NM_138384.4:c.434G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138384.4(MTG1):​c.434G>A​(p.Cys145Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000152 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C145R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: MTG1 NM_138384.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17263827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTG1	NM_138384.4	c.434G>A	p.Cys145Tyr	missense_variant	Exon 6 of 11	ENST00000317502.11	NP_612393.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTG1	ENST00000317502.11	c.434G>A	p.Cys145Tyr	missense_variant	Exon 6 of 11	1	NM_138384.4	ENSP00000323047.6
MTG1	ENST00000477902.6	c.311G>A	p.Cys104Tyr	missense_variant	Exon 6 of 11	3		ENSP00000475596.1
ENSG00000254536	ENST00000468317.3	n.*358G>A		non_coding_transcript_exon_variant	Exon 11 of 16	5		ENSP00000436767.2
ENSG00000254536	ENST00000468317.3	n.*358G>A		3_prime_UTR_variant	Exon 11 of 16	5		ENSP00000436767.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251418 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135880

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 221 AN: 1461844 Hom.: 1 Cov.: 31 AF XY: 0.000139 AC XY: 101 AN XY: 727226

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00332

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74488

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

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 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.434G>A (p.C145Y) 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 434, causing the cysteine (C) at amino acid position 145 to be replaced by a tyrosine (Y). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	.;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Benign	0.24
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.88	T;T;T
Polyphen		0.98	.;.;D
Vest4		0.62
MVP		0.68
MPC		0.32
ClinPred		0.23	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.69

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: rs146230872; hg19: chr10-135213046;