RPS19

Chr 19AD

ribosomal protein S19

Also known as: DBA, DBA1, LOH19CR1, S19, eS19

NCBI Gene: 6223 ENSG00000105372 UniProt: P39019

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 ribosomal protein that is a component of the 40S subunit. The protein belongs to the S19E family of ribosomal proteins. It is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia (DBA), a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors, in a subset of patients. This suggests a possible extra-ribosomal function for this gene in erythropoietic differentiation and proliferation, in addition to its ribosomal function. Higher expression levels of this gene in some primary colon carcinomas compared to matched normal colon tissues has been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Diamond-Blackfan anemia 1MIM #105650

Active trials

Pathogenic / LP

305

ClinVar variants

Pubs (1 yr)

1.5

Missense Z

0.37

LOEUF

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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ClinVar Variants

94 Pathogenic / Likely Pathogenic· 101 VUS of 305 total submissions

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Clinical Trials

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

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GeneReview available — RPS19

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE0.00 (0.00–0.37)

0≤0.351.4

Missense OE0.57 (0.46–0.72)

0≤0.61.4

Synonymous OE1.44

0≤1.21.6

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

LOFDN

Badonyi & Marsh 2024 ↗

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 · 43% of P/LP variants are LoF · LOEUF 0.37

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.PMID:20606162

LOFp53-Independent cell cycle and erythroid differentiation defects in murine embryonic stem cells haploinsufficient for Diamond Blackfan anemia-proteins: RPS19 versus RPL5.PMID:24558476

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