6-43675499-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018135.4(MRPS18A):c.371G>A(p.Arg124Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

MRPS18A
NM_018135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41334003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS18A	NM_018135.4 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 6	ENST00000372133.8	NP_060605.1	Q9NVS2-1
MRPS18A	NM_001193343.2 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 5		NP_001180272.1	Q9NVS2-3
MRPS18A	XM_006715134.4 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 5		XP_006715197.1	Q9NVS2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPS18A	ENST00000372133.8 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 6	1	NM_018135.4	ENSP00000361206.3	Q9NVS2-1
MRPS18A	ENST00000427312.1 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 5	1		ENSP00000398679.1	Q5QPA5
MRPS18A	ENST00000372116.5 link	c.371G>A	p.Arg124Gln	missense_variant	Exon 4 of 5	2		ENSP00000361188.1	Q9NVS2-3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251378

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000718

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371G>A (p.R124Q) alteration is located in exon 4 (coding exon 4) of the MRPS18A gene. This alteration results from a G to A substitution at nucleotide position 371, causing the arginine (R) at amino acid position 124 to be replaced by a glutamine (Q). 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

Benign

0.29

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.051

T;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.15

N;N;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.074

T;T;D

Sift4G

Benign

0.091

T;T;.

Polyphen

1.0

D;.;.

Vest4

0.87

MVP

0.37

MPC

0.53

ClinPred

0.70

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.66

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