rs569406382

Variant names:

• chr6-43675532-C-A
• rs569406382
• NM_018135.4:c.338G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-43675532-C-A
• chr6-43675532-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018135.4(MRPS18A):​c.338G>T​(p.Arg113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R113H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MRPS18A NM_018135.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.684
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.338G>T	p.Arg113Leu	missense	Exon 4 of 6	NP_060605.1	Q9NVS2-1
	MRPS18A	NM_001193343.2		c.338G>T	p.Arg113Leu	missense	Exon 4 of 5	NP_001180272.1	Q9NVS2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS18A	ENST00000372133.8	TSL:1 MANE Select	c.338G>T	p.Arg113Leu	missense	Exon 4 of 6	ENSP00000361206.3	Q9NVS2-1
	MRPS18A	ENST00000427312.1	TSL:1	c.338G>T	p.Arg113Leu	missense	Exon 4 of 5	ENSP00000398679.1	Q5QPA5
	MRPS18A	ENST00000924155.1		c.230G>T	p.Arg77Leu	missense	Exon 3 of 4	ENSP00000594214.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.68
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.16
Sift	Benign	0.066	T
Sift4G	Benign	0.079	T
Polyphen		0.026	B
Vest4		0.51
MutPred		0.71		Loss of disorder (P = 0.044)
MVP		0.35
MPC		0.63
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.83
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs569406382; hg19: chr6-43643269;