6-43671895-C-G

Variant names:

• chr6-43671895-C-G
• rs544410027
• NM_018135.4:c.458G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018135.4(MRPS18A):​c.458G>C​(p.Arg153Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R153L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRPS18A NM_018135.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.01
• Publications: 2 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]

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

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.458G>C	p.Arg153Pro	missense	Exon 6 of 6	NP_060605.1	Q9NVS2-1
	RSPH9	NM_152732.5	MANE Select	c.*946C>G		3_prime_UTR	Exon 5 of 5	NP_689945.2
	RSPH9	NM_001424119.1		c.*908C>G		3_prime_UTR	Exon 6 of 6	NP_001411048.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS18A	ENST00000372133.8	TSL:1 MANE Select	c.458G>C	p.Arg153Pro	missense	Exon 6 of 6	ENSP00000361206.3	Q9NVS2-1
	MRPS18A	ENST00000427312.1	TSL:1	c.680G>C	p.Arg227Pro	missense	Exon 5 of 5	ENSP00000398679.1	Q5QPA5
	RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.*946C>G		3_prime_UTR	Exon 5 of 5	ENSP00000361236.4	Q9H1X1-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238346 AF XY: 0.00000773

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456982 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724504

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109604

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.43		Loss of MoRF binding (P = 0.0093)
MVP		0.65
MPC		0.66
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.87
Mutation Taster		=50/50

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: rs544410027; hg19: chr6-43639632;