19-17863001-C-T

Variant names:

• chr19-17863001-C-T
• rs150231641
• NM_000980.4:c.412C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000980.4(RPL18A):​c.412C>T​(p.Arg138Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,611,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: RPL18A NM_000980.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

RPL18A (HGNC:10311): (ribosomal protein L18a) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L18AE family of ribosomal proteins that is a component of the 60S subunit. The encoded protein may play a role in viral replication by interacting with the hepatitis C virus internal ribosome entry site (IRES). This gene is co-transcribed with the U68 snoRNA, located within the third intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL18A	NM_000980.4	c.412C>T	p.Arg138Cys	missense_variant	Exon 4 of 5	ENST00000222247.10	NP_000971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL18A	ENST00000222247.10	c.412C>T	p.Arg138Cys	missense_variant	Exon 4 of 5	1	NM_000980.4	ENSP00000222247.4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152140 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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000769 AC: 19 AN: 247018 AF XY: 0.0000894

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: 0.0000464

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000788 AC: 115 AN: 1459638 Hom.: 0 Cov.: 30 AF XY: 0.0000744 AC XY: 54 AN XY: 726152

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33426

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26120

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39688

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86184

Gnomad4 FIN exome AF: 0.0000188 AC: 1 AN: 53320

Gnomad4 NFE exome AF: 0.0000954 AC: 106 AN: 1110980

Gnomad4 Remaining exome AF: 0.0000498 AC: 3 AN: 60246

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74298

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000176 AC: 0.000176408 AN: 0.000176408

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412C>T (p.R138C) alteration is located in exon 4 (coding exon 4) of the RPL18A gene. This alteration results from a C to T substitution at nucleotide position 412, causing the arginine (R) at amino acid position 138 to be replaced by a cysteine (C). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.;T;T
Eigen	Benign	0.057
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	2.0	M;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	D;.;.;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.0090	B;.;.;.;.
Vest4		0.91
MVP		0.64
MPC		1.2
ClinPred		0.50	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.71
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs150231641; hg19: chr19-17973810;