RPS3

Chr 11

ribosomal protein S3

Also known as: S3, uS3

NCBI Gene: 6188 ENSG00000149273 UniProt: P23396

RPS3 encodes a ribosomal protein component of the 40S ribosomal subunit essential for protein synthesis, and also functions as an endonuclease involved in DNA repair, transcriptional regulation, and apoptosis. Mutations cause Diamond-Blackfan anemia, an autosomal dominant ribosomopathy characterized by bone marrow failure, growth retardation, and congenital anomalies typically presenting in infancy. The gene is highly constrained against loss-of-function variants (pLI=0.92, LOEUF=0.38), reflecting its essential cellular functions.

ResearchSummary from RefSeq, UniProt

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, where it forms part of the domain where translation is initiated. The protein belongs to the S3P family of ribosomal proteins. Studies of the mouse and rat proteins have demonstrated that the protein has an extraribosomal role as an endonuclease involved in the repair of UV-induced DNA damage. The protein appears to be located in both the cytoplasm and nucleus but not in the nucleolus. Higher levels of expression of this gene in colon adenocarcinomas and adenomatous polyps compared to adjacent normal colonic mucosa have been observed. This gene is co-transcribed with the small nucleolar RNA genes U15A and U15B, which are located in its first and fifth introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.920

Z-score 3.01

OE 0.08 (0.03–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.78Z-score

OE missense 0.37 (0.30–0.46)

57 obs / 154.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.38)

0≤0.351.4

Missense OE?0.37 (0.30–0.46)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 1 / 12.5Missense obs/exp: 57 / 154.1Syn Z: -1.29

Background carrier burden — how many people carry a rare variant somewhere in RPS3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 980

158 rare PASS variants

Rare truncating (LoF)

1 in 11,000

12 rare PASS variants

Rare synonymous (reference)

1 in 470

103 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RPS3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 1,600	1 in 8,900
South Asian	~43k	1 in 390	1 in 1,900
Remaining (unassigned)	~30k	1 in 470	≈ 1 in 30,000
European (Finnish)	~27k	1 in 810	none seen
Admixed American	~22k	1 in 1,000	≈ 1 in 22,000
African / African American	~21k	1 in 410	none seen
East Asian	~20k	1 in 920	≈ 1 in 9,900
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,884	1 in 260	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 6.? see exons ↓