RPS19

Chr 19AD

ribosomal protein S19

ENSG00000105372 UniProt: P39019 OMIM: 603474

RPS19 encodes a ribosomal protein that is a component of the small 40S ribosomal subunit and is required for pre-rRNA processing and maturation of ribosomal subunits. Mutations cause Diamond-Blackfan anemia, a constitutional anemia characterized by absent or decreased red blood cell precursors, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.92), reflecting its essential role in protein synthesis.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Component of the small ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399). Required for pre-rRNA processing and maturation of 40S ribosomal subunits (PubMed:16990592). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797)

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.371 OMIM phenotype

Clinical Summary— RPS19

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Gene-Disease Validity (ClinGen)

Diamond-Blackfan anemia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.37LOEUF

pLI 0.921

Z-score 2.64

OE 0.00 (0.00–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.45Z-score

OE missense 0.57 (0.46–0.72)

53 obs / 92.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.37)

0≤0.351.4

Missense OE?0.57 (0.46–0.72)

0≤0.61.4

Synonymous OE?1.44

0≤1.21.6

LoF obs/exp: 0 / 8.1Missense obs/exp: 53 / 92.2Syn Z: -2.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRPS19-related Diamond-Blackfan anemiaLOFAD

This gene — mechanism propensity

0.4190th %ile

GOF

0.2099th %ile

LOF

0.74top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.37 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNA transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia.1

LOFp53-Independent cell cycle and erythroid differentiation defects in murine embryonic stem cells haploinsufficient for Diamond Blackfan anemia-proteins: RPS19 versus RPL5.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References