Diamond-Blackfan anemia 6

Summary

Diamond-Blackfan anemia 6 (MONDO:0012937) is a disease caused by RPL5 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: RPL5 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 124

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Diamond-Blackfan anemia 6
Mondo ID	MONDO:0012937
MeSH	C538442
OMIM	612561
DOID	DOID:0111879
NCIT	C176915
UMLS	C2931850
MedGen	419918
GARD	0015568
Is cancer (heuristic)	no

Also known as: DBA6 · Diamond-Blackfan anaemia caused by mutation in RPL5 · Diamond-Blackfan Anaemia type 6 · Diamond-Blackfan anemia 6 · Diamond-Blackfan anemia caused by mutation in RPL5 · Diamond-Blackfan Anemia type 6 · RPL5 Diamond-Blackfan anaemia · RPL5 Diamond-Blackfan anemia

Data availability: 124 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 6

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 4, Diamond-Blackfan anemia 5, 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

124 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 14 pathogenic, 13 benign/likely benign, 13 likely pathogenic, 9 conflicting classifications of pathogenicity, 8 likely benign, 8 benign, 5 pathogenic/likely pathogenic, 1 risk factor, 1 association

ClinVar	Variant (HGVS)	Gene	Classification	Review
981207	GRCh37/hg19 1p22.1(chr1:92405898-94018197)x1	BRDT	Pathogenic	no assertion criteria provided
100638	NM_000969.5(RPL5):c.244G>T (p.Glu82Ter)	DIPK1A	Pathogenic	criteria provided, single submitter
100639	NM_000969.5(RPL5):c.664C>T (p.Gln222Ter)	DIPK1A	Pathogenic	criteria provided, single submitter
1030925	NM_000969.5(RPL5):c.459_460insTGAA (p.Thr154Ter)	DIPK1A	Pathogenic	criteria provided, single submitter
1476888	NM_000969.5(RPL5):c.527+1G>T	DIPK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1779974	NM_000969.5(RPL5):c.178_179del (p.Ile60fs)	DIPK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690941	NM_000969.5(RPL5):c.236del (p.Tyr79fs)	DIPK1A	Pathogenic	criteria provided, single submitter
4077473	NM_000969.5(RPL5):c.115C>T (p.Gln39Ter)	DIPK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531714	NM_000969.5(RPL5):c.336del (p.Arg112fs)	DIPK1A	Pathogenic	criteria provided, single submitter
579583	NM_000969.5(RPL5):c.169_172del (p.Asn57fs)	DIPK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
6179	NM_000969.5(RPL5):c.67C>T (p.Arg23Ter)	DIPK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
6182	NM_000969.5(RPL5):c.235dup (p.Tyr79fs)	DIPK1A	Pathogenic	no assertion criteria provided
6184	NM_000969.5(RPL5):c.73+2T>G	DIPK1A	Pathogenic	no assertion criteria provided
692051	NM_000969.5(RPL5):c.692dup (p.Thr232fs)	DIPK1A	Pathogenic	criteria provided, single submitter
1325015	NM_000969.5(RPL5):c.155_156dup (p.Val53Ter)	RPL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803120	NM_000969.5(RPL5):c.3+1G>A	RPL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6183	RPL5, 5-BP DEL/39-BP INS, NT498	RPL5	Pathogenic	no assertion criteria provided
662012	NM_000969.5(RPL5):c.175_176del (p.Asp59fs)	RPL5	Pathogenic	criteria provided, multiple submitters, no conflicts
930202	NM_000969.5(RPL5):c.268del (p.Val90fs)	RPL5	Pathogenic	no assertion criteria provided
1526098	NM_000969.5(RPL5):c.613dup (p.Ala205fs)	DIPK1A	Likely pathogenic	criteria provided, single submitter
1527850	NM_000969.5(RPL5):c.122_144del (p.Lys41fs)	DIPK1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705363	NM_000969.5(RPL5):c.189+1G>C	DIPK1A	Likely pathogenic	criteria provided, single submitter
1705631	NM_000969.5(RPL5):c.509del (p.Gly170fs)	DIPK1A	Likely pathogenic	criteria provided, single submitter
2915334	NM_000969.5(RPL5):c.4-1G>A	DIPK1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3358914	NM_000969.5(RPL5):c.9del (p.Phe3fs)	DIPK1A	Likely pathogenic	criteria provided, single submitter
4076388	NM_000969.5(RPL5):c.604C>T (p.Gln202Ter)	DIPK1A	Likely pathogenic	criteria provided, single submitter
4077474	NM_000969.5(RPL5):c.189+1G>A	DIPK1A	Likely pathogenic	criteria provided, single submitter
4293207	NM_000969.5(RPL5):c.255del (p.Lys85fs)	DIPK1A	Likely pathogenic	criteria provided, single submitter
4531713	NM_000969.5(RPL5):c.190-2A>G	DIPK1A	Likely pathogenic	criteria provided, single submitter
4846923	NM_000969.5(RPL5):c.397dup (p.Glu133fs)	DIPK1A	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
RPL5	Definitive	Autosomal dominant	Diamond-Blackfan anemia 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPL5	Orphanet:124	Diamond-Blackfan anemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPL5	HGNC:10360	ENSG00000122406	P46777	Large ribosomal subunit protein uL18	gencc,clinvar
BRDT	HGNC:1105	ENSG00000137948	Q58F21	Bromodomain testis-specific protein	clinvar
DIPK1A	HGNC:32213	ENSG00000154511	Q5T7M9	Divergent protein kinase domain 1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPL5	Large ribosomal subunit protein uL18	Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
BRDT	Bromodomain testis-specific protein	Testis-specific chromatin protein that specifically binds histone H4 acetylated at ‘Lys-5’ and ‘Lys-8’ (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPL5	Other/Unknown	no		Rbsml_uL18_euk_arc, Ribosomal_uL18_C_euk, Ribosomal_L18
BRDT	Other/Unknown	no		Bromodomain, Bromodomain_CS, NET_dom
DIPK1A	Kinase	yes		FAM69_kinase_dom, FAM69_N

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
parietal pleura	1
primordial germ cell in gonad	1
left testis	1
right testis	1
testis	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPL5	292	ubiquitous	marker	germinal epithelium of ovary, primordial germ cell in gonad, parietal pleura
BRDT	116	tissue_specific	marker	left testis, right testis, testis
DIPK1A	275	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL5	6,028
BRDT	1,578
DIPK1A	575

Intra-cohort edges

A	B	Sources
DIPK1A	RPL5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL5	P46777	184
BRDT	Q58F21	21

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DIPK1A	Q5T7M9	83.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 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
Peptide chain elongation	1	126.9×	0.012	RPL5
Viral mRNA Translation	1	126.9×	0.012	RPL5
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	125.5×	0.012	RPL5
Selenocysteine synthesis	1	120.2×	0.012	RPL5
Eukaryotic Translation Termination	1	120.2×	0.012	RPL5
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	117.7×	0.012	RPL5
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	117.7×	0.012	RPL5
Formation of a pool of free 40S subunits	1	112.0×	0.012	RPL5
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	110.9×	0.012	RPL5
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	1	106.7×	0.012	RPL5
L13a-mediated translational silencing of Ceruloplasmin expression	1	101.1×	0.012	RPL5
SRP-dependent cotranslational protein targeting to membrane	1	100.2×	0.012	RPL5
GTP hydrolysis and joining of the 60S ribosomal subunit	1	100.2×	0.012	RPL5
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	97.6×	0.012	RPL5
Regulation of expression of SLITs and ROBOs	1	69.2×	0.015	RPL5
Major pathway of rRNA processing in the nucleolus and cytosol	1	61.7×	0.016	RPL5

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
ribosomal large subunit assembly	1	702.2×	0.013	RPL5
sperm DNA condensation	1	443.5×	0.013	BRDT
negative regulation of ubiquitin-dependent protein catabolic process	1	421.3×	0.013	RPL5
male meiosis I	1	290.6×	0.013	BRDT
male meiotic nuclear division	1	271.8×	0.013	BRDT
ribosomal large subunit biogenesis	1	221.7×	0.013	RPL5
regulation of signal transduction by p53 class mediator	1	191.5×	0.013	RPL5
positive regulation of translation	1	113.9×	0.018	RPL5
regulation of RNA splicing	1	109.4×	0.018	BRDT
cytoplasmic translation	1	92.6×	0.019	RPL5
rRNA processing	1	70.8×	0.023	RPL5
translation	1	51.4×	0.029	RPL5
RNA splicing	1	44.1×	0.031	BRDT
mRNA processing	1	39.4×	0.032	BRDT
chromatin remodeling	1	36.5×	0.033	BRDT
positive regulation of gene expression	1	19.4×	0.057	BRDT
regulation of DNA-templated transcription	1	15.8×	0.066	BRDT
regulation of transcription by RNA polymerase II	1	5.8×	0.164	BRDT

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
RPL5	GENTAMICIN SULFATE
BRDT	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRDT	12	4
RPL5	1	4
DIPK1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPL5
FEDRATINIB	4	BRDT
FOSTAMATINIB	4	BRDT
VOLASERTIB	3	BRDT
DINACICLIB	3	BRDT
APABETALONE	3	BRDT
ALVOCIDIB	3	BRDT
MOLIBRESIB	2	BRDT
MIVEBRESIB	2	BRDT
BI-2536	2	BRDT
AZD-5153	1	BRDT
ABBV-744	1	BRDT
INOBRODIB	1	BRDT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BRDT	348	Binding:330, Functional:14, ADMET:4
RPL5	90	Binding:90

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BRDT	348

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

13 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	RPL5
FEDRATINIB	4	BRDT
FOSTAMATINIB	4	BRDT
VOLASERTIB	3	BRDT
DINACICLIB	3	BRDT
APABETALONE	3	BRDT
ALVOCIDIB	3	BRDT
MOLIBRESIB	2	BRDT
MIVEBRESIB	2	BRDT
BI-2536	2	BRDT
AZD-5153	1	BRDT
ABBV-744	1	BRDT
INOBRODIB	1	BRDT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RPL5, BRDT
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	DIPK1A
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)
DIPK1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.