Diamond-Blackfan anemia 4

Summary

Diamond-Blackfan anemia 4 (MONDO:0012924) is a disease caused by RPS17 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RPS17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Diamond-Blackfan anemia 4
Mondo ID	MONDO:0012924
MeSH	C567281
OMIM	612527
DOID	DOID:0111890
NCIT	C176913
UMLS	C2675860
MedGen	393906
GARD	0015561
Is cancer (heuristic)	no

Also known as: DBA4 · Diamond-Blackfan anaemia caused by mutation in RPS17 · Diamond-Blackfan Anaemia type 4 · Diamond-Blackfan anemia 4 · Diamond-Blackfan anemia caused by mutation in RPS17 · Diamond-Blackfan Anemia type 4 · RPS17 Diamond-Blackfan anaemia · RPS17 Diamond-Blackfan anemia

Data availability: 21 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › pure red-cell aplasia › Diamond-Blackfan anemia › Diamond-Blackfan anemia 4

Related subtypes (21): Diamond-Blackfan anemia 1, Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, Diamond-Blackfan anemia 2, Diamond-Blackfan anemia 15 with mandibulofacial dysostosis, Diamond-Blackfan anemia 3, Diamond-Blackfan anemia 5, Diamond-Blackfan anemia 6, Diamond-Blackfan anemia 7, Diamond-Blackfan anemia 8, Diamond-Blackfan anemia 9, Diamond-Blackfan anemia 10, Diamond-Blackfan anemia 11, Diamond-Blackfan anemia 12, Diamond-Blackfan anemia 13, Diamond-Blackfan anemia 21, Diamond-Blackfan anemia 18, Diamond-Blackfan anemia 19, Diamond-Blackfan anemia 20, Diamond-Blackfan anemia 16, Diamond-Blackfan anemia 17, Diamond-Blackfan anemia 22

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 5 pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579211	GRCh38/hg38 15q25.2(chr15:82130136-82727529)x1	AP3B2	Pathogenic	criteria provided, single submitter
100625	NM_001021.6(RPS17):c.159T>G (p.Tyr53Ter)	RPS17	Pathogenic	no assertion criteria provided
12999	NM_001021.6(RPS17):c.2T>G (p.Met1Arg)	RPS17	Pathogenic	criteria provided, single submitter
13000	NM_001021.6(RPS17):c.201_202del (p.Gly68fs)	RPS17	Pathogenic	no assertion criteria provided
1784170	NM_001021.6(RPS17):c.1A>G (p.Met1Val)	RPS17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88976	NG_009890.2:g.(5565_6559)_(8796_9460)del	RPS17	Pathogenic	no assertion criteria provided
2428499	NM_001021.6(RPS17):c.156-1G>A	RPS17	Likely pathogenic	criteria provided, single submitter
3577804	NM_001021.6(RPS17):c.403G>C (p.Val135Leu)	RPS17	Uncertain significance	criteria provided, single submitter
3577805	NM_001021.6(RPS17):c.334G>A (p.Gly112Ser)	RPS17	Uncertain significance	criteria provided, single submitter
3577806	NM_001021.6(RPS17):c.328G>T (p.Asp110Tyr)	RPS17	Uncertain significance	criteria provided, single submitter
3577807	NM_001021.6(RPS17):c.261+3A>G	RPS17	Uncertain significance	criteria provided, single submitter
3577808	NM_001021.6(RPS17):c.165G>C (p.Thr55=)	RPS17	Uncertain significance	criteria provided, single submitter
3577810	NM_001021.6(RPS17):c.160G>C (p.Val54Leu)	RPS17	Uncertain significance	criteria provided, single submitter
3577811	NM_001021.6(RPS17):c.160G>A (p.Val54Ile)	RPS17	Uncertain significance	criteria provided, single submitter
3577812	NM_001021.6(RPS17):c.155+3G>A	RPS17	Uncertain significance	criteria provided, single submitter
3577813	NM_001021.6(RPS17):c.99C>T (p.Arg33=)	RPS17	Uncertain significance	criteria provided, single submitter
3577814	NM_001021.6(RPS17):c.65C>T (p.Thr22Met)	RPS17	Uncertain significance	criteria provided, single submitter
3577815	NM_001021.6(RPS17):c.3+7G>A	RPS17	Uncertain significance	criteria provided, single submitter
4076389	NM_001021.6(RPS17):c.40C>T (p.Arg14Trp)	RPS17	Uncertain significance	criteria provided, single submitter
1223515	NM_001021.6(RPS17):c.312A>G (p.Glu104=)	RPS17	Likely benign	criteria provided, multiple submitters, no conflicts
506484	NM_001021.6(RPS17):c.328-7G>A	RPS17	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RPS17	Strong	Autosomal dominant	Diamond-Blackfan anemia 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPS17	Orphanet:124	Diamond-Blackfan anemia
AP3B2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS17	HGNC:10397	ENSG00000182774	P08708	Small ribosomal subunit protein eS17	gencc,clinvar
AP3B2	HGNC:567	ENSG00000103723	Q13367	AP-3 complex subunit beta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPS17	Small ribosomal subunit protein eS17	Component of the small ribosomal subunit.
AP3B2	AP-3 complex subunit beta-2	Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS17	Other/Unknown	no		Ribosomal_eS17, Ribosomal_eS17_CS, Ribosomal_eS17_sf
AP3B2	Antibody/Immunoglobulin	yes		Clathrin/coatomer_adapt-like_N, ARM-like, Clathrin_app_Ig-like_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
ganglionic eminence	1
left ovary	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS17	134	ubiquitous	marker	ganglionic eminence, corpus callosum, left ovary
AP3B2	202	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPS17	3,004
AP3B2	1,738

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPS17	P08708	212

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AP3B2	Q13367	75.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Eukaryotic Translation Initiation	1	308.6×	0.016	RPS17
Cap-dependent Translation Initiation	1	308.6×	0.016	RPS17
SARS-CoV-1 modulates host translation machinery	1	308.6×	0.016	RPS17
Eukaryotic Translation Elongation	1	278.5×	0.016	RPS17
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1	271.9×	0.016	RPS17
Nonsense-Mediated Decay (NMD)	1	233.1×	0.016	RPS17
SARS-CoV-2 modulates host translation machinery	1	223.9×	0.016	RPS17
Influenza Viral RNA Transcription and Replication	1	215.5×	0.016	RPS17
Formation of the ternary complex, and subsequently, the 43S complex	1	215.5×	0.016	RPS17
Selenoamino acid metabolism	1	196.9×	0.016	RPS17
Translation initiation complex formation	1	190.3×	0.016	RPS17
Ribosomal scanning and start codon recognition	1	190.3×	0.016	RPS17
Influenza Infection	1	175.7×	0.016	RPS17
SARS-CoV-1-host interactions	1	175.7×	0.016	RPS17
Cellular response to starvation	1	165.5×	0.016	RPS17
rRNA processing in the nucleus and cytosol	1	160.8×	0.016	RPS17
rRNA processing	1	146.4×	0.016	RPS17
SARS-CoV-1 Infection	1	142.8×	0.016	RPS17
Peptide chain elongation	1	126.9×	0.016	RPS17
Viral mRNA Translation	1	126.9×	0.016	RPS17
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	125.5×	0.016	RPS17
Signaling by ROBO receptors	1	124.1×	0.016	RPS17
Selenocysteine synthesis	1	120.2×	0.016	RPS17
Eukaryotic Translation Termination	1	120.2×	0.016	RPS17
SARS-CoV-2-host interactions	1	119.0×	0.016	RPS17
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	117.7×	0.016	RPS17
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	117.7×	0.016	RPS17
Formation of a pool of free 40S subunits	1	112.0×	0.016	RPS17
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	110.9×	0.016	RPS17
L13a-mediated translational silencing of Ceruloplasmin expression	1	101.1×	0.016	RPS17

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic vesicle coating	1	1685.2×	0.005	AP3B2
clathrin-coated vesicle cargo loading, AP-3-mediated	1	1203.7×	0.005	AP3B2
erythrocyte homeostasis	1	648.1×	0.005	RPS17
synaptic vesicle recycling	1	601.9×	0.005	AP3B2
anterograde synaptic vesicle transport	1	495.6×	0.005	AP3B2
anterograde axonal transport	1	290.6×	0.007	AP3B2
translational initiation	1	179.3×	0.010	RPS17
ribosomal small subunit biogenesis	1	113.9×	0.014	RPS17
cytoplasmic translation	1	92.6×	0.016	RPS17
rRNA processing	1	70.8×	0.018	RPS17
translation	1	51.4×	0.022	RPS17
vesicle-mediated transport	1	48.1×	0.022	AP3B2
intracellular protein transport	1	32.4×	0.031	AP3B2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RPS17	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPS17	1	4
AP3B2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPS17

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RPS17	90	Binding:90

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
GENTAMICIN SULFATE	4	RPS17

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RPS17
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	AP3B2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AP3B2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.