Genetic Variant RPL18A:p.Arg111Leu (chr19-17862921-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000980.4(RPL18A):c.332G>T(p.Arg111Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,924 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. R111Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RPL18A
NM_000980.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.86

Publications

0 publications found

Variant links:

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]

RPL18A links:

SNORA68 (HGNC:10225): (small nucleolar RNA, H/ACA box 68)

SNORA68 links:

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ACMG classification

Classification was made for transcript

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, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL18A	NM_000980.4 link	c.332G>T	p.Arg111Leu	missense_variant	Exon 4 of 5	ENST00000222247.10	NP_000971.1	Q02543
SNORA68	NR_000012.1 link	n.*201G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL18A	ENST00000222247.10 link	c.332G>T	p.Arg111Leu	missense_variant	Exon 4 of 5	1	NM_000980.4	ENSP00000222247.4		Q02543

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4878

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109844

Other (OTH)

AF:

0.0000166

AC:

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.;.;T;T

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.024

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.76

D;D;D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.6

M;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.4

D;.;.;.;.

REVEL

Uncertain

0.50

Sift

Benign

0.038

D;.;.;.;.

Sift4G

Benign

0.072

T;T;D;T;T

Polyphen

0.0090

B;.;.;.;.

Vest4

0.93

MutPred

0.52

Loss of MoRF binding (P = 0.0124);Loss of MoRF binding (P = 0.0124);.;.;.;

MVP

0.74

MPC

1.1

ClinPred

0.98

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.79

gMVP

0.73

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-17862921-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over