Genetic Variant MRPL15:p.Tyr179Cys (chr8-54142769-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014175.4(MRPL15):c.536A>G(p.Tyr179Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,828 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: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MRPL15
NM_014175.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.15

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:

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ACMG classification

Classification made for transcript

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, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL15	NM_014175.4 link	c.536A>G	p.Tyr179Cys	missense_variant	Exon 4 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.536A>G	p.Tyr179Cys	missense_variant	Exon 4 of 5	1	NM_014175.4	ENSP00000260102.4	Q9P015
MRPL15	ENST00000522521.2 link	c.359A>G	p.Tyr120Cys	missense_variant	Exon 4 of 5	5		ENSP00000429252.2	E5RIZ4
MRPL15	ENST00000519831.5 link	c.536A>G	p.Tyr179Cys	missense_variant	Exon 4 of 4	2		ENSP00000428581.1	E5RHF4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727204

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

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

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536A>G (p.Y179C) alteration is located in exon 4 (coding exon 4) of the MRPL15 gene. This alteration results from a A to G substitution at nucleotide position 536, causing the tyrosine (Y) at amino acid position 179 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

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.2

M;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.5

D;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.80

Loss of phosphorylation at Y179 (P = 0.1957);Loss of phosphorylation at Y179 (P = 0.1957);.;

MVP

0.79

MPC

0.64

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.88

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over