6-159797517-C-G

Variant names:

• chr6-159797517-C-G
• rs74992920
• NM_014161.5:c.470C>G

Variant summary

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

The NM_014161.5(MRPL18):​c.470C>G​(p.Ser157Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S157L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRPL18 NM_014161.5 missense, splice_region
• Scores: Splicing: ADA: 0.08864
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05
• Publications: 0 publications found

Genes affected

MRPL18 (HGNC:14477): (mitochondrial ribosomal protein L18) This nuclear gene encodes a protein component of the larger 39S subunit of mitochondrial ribosome. This protein may also aid in the import of nuclear-encoded 5S rRNA into mitochondria. Alternative splicing results in multiple transcript variants, most of which are not predicted to encode a protein. A pseudogene of this gene is found on chromosome 16. [provided by RefSeq, Jan 2016]

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_014161.5. 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
	MRPL18	NM_014161.5	MANE Select	c.470C>G	p.Ser157Trp	missense splice_region	Exon 3 of 4	NP_054880.2
	MRPL18	NM_001318817.2		c.322+148C>G		intron	N/A	NP_001305746.1
	MRPL18	NR_134860.1		n.732C>G		splice_region non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL18	ENST00000367034.5	TSL:1 MANE Select	c.470C>G	p.Ser157Trp	missense splice_region	Exon 3 of 4	ENSP00000356001.4	Q9H0U6
	MRPL18	ENST00000953331.1		c.497C>G	p.Ser166Trp	missense splice_region	Exon 3 of 4	ENSP00000623390.1
	MRPL18	ENST00000857674.1		c.300+170C>G		intron	N/A	ENSP00000527733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726628

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111316

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.40		Loss of disorder (P = 7e-04)
MVP		0.61
MPC		0.75
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.82
gMVP		0.72
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.089
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.13		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: rs74992920; hg19: chr6-160218549;