Genetic Variant MRPL15:p.Ile129Thr (chr8-54137390-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014175.4(MRPL15):c.386T>C(p.Ile129Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,852 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: 0.0000055 ( 0 hom. )

Consequence

MRPL15
NM_014175.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.95

Variant links:

Genes affected

MRPL15 (HGNC:14054): (mitochondrial ribosomal protein L15) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein that belongs to the EcoL15 ribosomal protein family. A pseudogene corresponding to this gene is found on chromosome 15q. [provided by RefSeq, Jul 2008]

MRPL15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MRPL15	NM_014175.4 link	c.386T>C	p.Ile129Thr	missense_variant	Exon 3 of 5	ENST00000260102.9	NP_054894.1	Q9P015

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPL15	ENST00000260102.9 link	c.386T>C	p.Ile129Thr	missense_variant	Exon 3 of 5	1	NM_014175.4	ENSP00000260102.4	Q9P015
MRPL15	ENST00000522521.2 link	c.209T>C	p.Ile70Thr	missense_variant	Exon 3 of 5	5		ENSP00000429252.2	E5RIZ4
MRPL15	ENST00000519831.5 link	c.386T>C	p.Ile129Thr	missense_variant	Exon 3 of 4	2		ENSP00000428581.1	E5RHF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251424

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727224

show subpopulations

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386T>C (p.I129T) alteration is located in exon 3 (coding exon 3) of the MRPL15 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the isoleucine (I) at amino acid position 129 to be replaced by a threonine (T). 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

0.70

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

D;D;.

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.025

D;T;D

Polyphen

0.51

P;.;.

Vest4

0.58

MutPred

0.47

Gain of disorder (P = 0.0267);Gain of disorder (P = 0.0267);.;

MVP

0.47

MPC

0.65

ClinPred

0.91

GERP RS

5.0

Varity_R

0.78

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over