Genetic Variant MRPS18A:p.Arg134Leu (chr6-43675247-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018135.4(MRPS18A):c.401G>T(p.Arg134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MRPS18A
NM_018135.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.35

Publications

0 publications found

Variant links:

Genes affected

MRPS18A (HGNC:14515): (mitochondrial ribosomal protein S18A) 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 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. A pseudogene corresponding to this gene is found on chromosome 3p. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]

MRPS18A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057304382).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS18A	NM_018135.4	MANE Select	c.401G>T	p.Arg134Leu	missense	Exon 5 of 6	NP_060605.1	Q9NVS2-1
	MRPS18A	NM_001193343.2		c.376+247G>T		intron	N/A	NP_001180272.1	Q9NVS2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPS18A	ENST00000372133.8	TSL:1 MANE Select	c.401G>T	p.Arg134Leu	missense	Exon 5 of 6	ENSP00000361206.3	Q9NVS2-1
MRPS18A	ENST00000427312.1	TSL:1	c.623G>T	p.Arg208Leu	missense	Exon 4 of 5	ENSP00000398679.1	Q5QPA5
MRPS18A	ENST00000924155.1		c.515G>T	p.Arg172Leu	missense	Exon 3 of 4	ENSP00000594214.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1372962

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673588

African (AFR)

AF:

0.00

AC:

AN:

30456

American (AMR)

AF:

0.00

AC:

AN:

30698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20254

East Asian (EAS)

AF:

0.00

AC:

AN:

38788

South Asian (SAS)

AF:

0.00

AC:

AN:

71116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069602

Other (OTH)

AF:

0.00

AC:

AN:

56504

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.5

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.037

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.65

M_CAP

Benign

0.0028

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-2.4

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.7

REVEL

Benign

0.026

Sift

Benign

0.32

Sift4G

Benign

0.27

Polyphen

0.0010

Vest4

0.11

MutPred

0.31

Loss of methylation at R134 (P = 0.0125)

MVP

0.24

MPC

0.15

ClinPred

0.23

GERP RS

-4.2

Varity_R

0.12

gMVP

0.45

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over