6-43671833-T-C

Position:

chr6-43671833-T-C

Variant summary

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

The NM_018135.4(MRPS18A):c.520A>G(p.Met174Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MRPS18A
NM_018135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.37

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:

RSPH9 (HGNC:21057): (radial spoke head component 9) This gene encodes a protein thought to be a component of the radial spoke head in motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia 12. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]

RSPH9 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:

RSPH9 (HGNC:):

RSPH9 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/exons	MANE	Protein	UniProt
MRPS18A	NM_018135.4 linkuse as main transcript	c.520A>G	p.Met174Val	missense_variant	6/6	ENST00000372133.8	NP_060605.1	Q9NVS2-1
RSPH9	NM_152732.5 linkuse as main transcript	c.*884T>C		3_prime_UTR_variant	5/5	ENST00000372163.5	NP_689945.2	Q9H1X1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS18A	ENST00000372133.8 linkuse as main transcript	c.520A>G	p.Met174Val	missense_variant	6/6	1	NM_018135.4	ENSP00000361206.3		Q9NVS2-1
RSPH9	ENST00000372163.5 linkuse as main transcript	c.*884T>C		3_prime_UTR_variant	5/5	1	NM_152732.5	ENSP00000361236.4		Q9H1X1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249162

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

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

Jun 29, 2022

The c.520A>G (p.M174V) alteration is located in exon 6 (coding exon 6) of the MRPS18A gene. This alteration results from a A to G substitution at nucleotide position 520, causing the methionine (M) at amino acid position 174 to be replaced by a valine (V). 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

0.37

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.68

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.13

T;T

Sift4G

Benign

0.17

T;.

Polyphen

0.084

B;.

Vest4

0.42

MVP

0.50

MPC

0.39

ClinPred

0.32

GERP RS

5.8

Varity_R

0.77

gMVP

0.73

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