6-43675247-C-T

Position:

chr6-43675247-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018135.4(MRPS18A):c.401G>A(p.Arg134Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,525,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MRPS18A
NM_018135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.35

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:

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019961119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS18A	NM_018135.4 linkuse as main transcript	c.401G>A	p.Arg134Gln	missense_variant	5/6	ENST00000372133.8	NP_060605.1	Q9NVS2-1
MRPS18A	XM_006715134.4 linkuse as main transcript	c.623G>A	p.Arg208Gln	missense_variant	4/5		XP_006715197.1	Q9NVS2-2
POLR1C	NM_001318876.2 linkuse as main transcript	c.945+145976C>T		intron_variant			NP_001305805.1	O15160-2
MRPS18A	NM_001193343.2 linkuse as main transcript	c.376+247G>A		intron_variant			NP_001180272.1	Q9NVS2-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MRPS18A	ENST00000372133.8 linkuse as main transcript	c.401G>A	p.Arg134Gln	missense_variant	5/6	1	NM_018135.4	ENSP00000361206.3	Q9NVS2-1
MRPS18A	ENST00000427312.1 linkuse as main transcript	c.623G>A	p.Arg208Gln	missense_variant	4/5	1		ENSP00000398679.1	Q5QPA5
MRPS18A	ENST00000372116.5 linkuse as main transcript	c.376+247G>A		intron_variant		2		ENSP00000361188.1	Q9NVS2-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000110

AC:

AN:

182064

Hom.:

AF XY:

0.000146

AC XY:

AN XY:

95754

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000574

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1372962

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

673588

show subpopulations

Gnomad4 AFR exome

AF:

0.000164

Gnomad4 AMR exome

AF:

0.000489

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000199

Gnomad4 NFE exome

AF:

0.00000841

Gnomad4 OTH exome

AF:

0.0000708

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000437

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.401G>A (p.R134Q) alteration is located in exon 5 (coding exon 5) of the MRPS18A gene. This alteration results from a G to A substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 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

0.067

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.3

DANN

Benign

0.97

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.013

Sift

Benign

0.74

T;T

Sift4G

Benign

0.74

T;.

Polyphen

0.0050

B;.

Vest4

0.066

MVP

0.32

MPC

0.14

ClinPred

0.027

GERP RS

-4.2

Varity_R

0.028

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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