Diamond-Blackfan anemia 5

Summary

Diamond-Blackfan anemia 5 (MONDO:0012925) is a disease caused by RPL35A (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: RPL35A (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 125

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Diamond-Blackfan anemia 5
Mondo ID	MONDO:0012925
MeSH	C567280
OMIM	612528
DOID	DOID:0111883
NCIT	C176914
UMLS	C2675859
MedGen	382705
GARD	0015562
Is cancer (heuristic)	no

Also known as: DBA5 · Diamond-Blackfan anaemia caused by mutation in RPL35A · Diamond-Blackfan Anaemia type 5 · Diamond-Blackfan anemia 5 · Diamond-Blackfan anemia caused by mutation in RPL35A · Diamond-Blackfan Anemia type 5 · RPL35A Diamond-Blackfan anaemia · RPL35A Diamond-Blackfan anemia

Data availability: 125 ClinVar variants · 2 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 5

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 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

125 retrieved; paginated sample, class counts are floors:

58 uncertain significance, 41 likely benign, 11 pathogenic, 5 benign/likely benign, 4 likely pathogenic, 4 conflicting classifications of pathogenicity, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4277371	Single allele	BDH1	Pathogenic	criteria provided, single submitter
13001	NM_000996.4(RPL35A):c.97G>A (p.Val33Ile)	DRC9	Pathogenic	no assertion criteria provided
13003	NM_000996.4(RPL35A):c.304C>T (p.Arg102Ter)	DRC9	Pathogenic	no assertion criteria provided
2579209	GRCh38/hg38 3q29(chr3:197681032-198111976)x1	DRC9	Pathogenic	criteria provided, single submitter
2747077	NM_000996.4(RPL35A):c.147del (p.Ala48_Tyr49insTer)	DRC9	Pathogenic	criteria provided, single submitter
3246899	NC_000003.11:g.(?197401889)(197682644_?)del	DRC9	Pathogenic	criteria provided, single submitter
469500	NC_000003.12:g.(?197950962)(197955779_?)del	DRC9	Pathogenic	criteria provided, single submitter
537236	NM_000996.4(RPL35A):c.212G>A (p.Trp71Ter)	DRC9	Pathogenic	criteria provided, single submitter
583098	NM_000996.4(RPL35A):c.118_119del (p.Glu40fs)	DRC9	Pathogenic	criteria provided, multiple submitters, no conflicts
647968	NC_000003.12:g.(?197950958)(197955783_?)del	DRC9	Pathogenic	criteria provided, single submitter
807674	NM_000996.4(RPL35A):c.258del (p.Lys87fs)	DRC9	Pathogenic	criteria provided, single submitter
1008059	NM_000996.4(RPL35A):c.89T>C (p.Ile30Thr)	DRC9	Likely pathogenic	criteria provided, single submitter
2423447	NC_000003.11:g.(?197680864)(197682644_?)del	DRC9	Likely pathogenic	criteria provided, single submitter
4720762	NM_000996.4(RPL35A):c.140G>T (p.Cys47Phe)	DRC9	Likely pathogenic	criteria provided, single submitter
843293	NM_000996.4(RPL35A):c.164+1G>A	DRC9	Likely pathogenic	criteria provided, single submitter
1015847	NM_000996.4(RPL35A):c.12-5C>G	DRC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13002	NM_000996.4(RPL35A):c.79CTT[1] (p.Leu28del)	DRC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1490681	NM_000996.4(RPL35A):c.270C>T (p.Ser90=)	DRC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1723464	NM_000996.4(RPL35A):c.125A>G (p.Tyr42Cys)	DRC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060385	NM_000996.4(RPL35A):c.113A>G (p.Glu38Gly)	DRC9	Uncertain significance	criteria provided, single submitter
1379208	NM_000996.4(RPL35A):c.59A>G (p.Asn20Ser)	DRC9	Uncertain significance	criteria provided, single submitter
1407481	NM_000996.4(RPL35A):c.35C>T (p.Ala12Val)	DRC9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1443120	NM_000996.4(RPL35A):c.28A>G (p.Ile10Val)	DRC9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1463153	NM_000996.4(RPL35A):c.320C>T (p.Pro107Leu)	DRC9	Uncertain significance	criteria provided, single submitter
1480694	NM_000996.4(RPL35A):c.77C>T (p.Ala26Val)	DRC9	Uncertain significance	criteria provided, single submitter
1500352	NM_000996.4(RPL35A):c.253C>G (p.Arg85Gly)	DRC9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1519866	NM_000996.4(RPL35A):c.101A>T (p.Tyr34Phe)	DRC9	Uncertain significance	criteria provided, single submitter
2163177	NM_000996.4(RPL35A):c.309+3G>C	DRC9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2173792	NM_000996.4(RPL35A):c.158C>G (p.Ala53Gly)	DRC9	Uncertain significance	criteria provided, single submitter
2435474	NM_000996.4(RPL35A):c.16T>C (p.Trp6Arg)	DRC9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
RPL35A	Strong	Autosomal dominant	Diamond-Blackfan anemia 5	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPL35A	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
RPL35A	HGNC:10345	ENSG00000182899	P18077	Large ribosomal subunit protein eL33	gencc,clinvar
BDH1	HGNC:1027	ENSG00000161267	Q02338	D-beta-hydroxybutyrate dehydrogenase, mitochondrial	clinvar
DRC9	HGNC:25251	ENSG00000114473	Q9H095	Dynein regulatory complex protein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPL35A	Large ribosomal subunit protein eL33	Component of the large ribosomal subunit.
DRC9	Dynein regulatory complex protein 9	Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPL35A	Other/Unknown	no		Ribosomal_eL33, Transl_B-barrel_sf, Ribosomal_eL33_CS
BDH1	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
DRC9	Other/Unknown	no		IQ_motif_EF-hand-BS, IQCG

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
left ovary	1
skin of hip	1
tendon of biceps brachii	1
liver	1
mucosa of transverse colon	1
right lobe of liver	1
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPL35A	288	ubiquitous	marker	tendon of biceps brachii, left ovary, skin of hip
BDH1	134	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon
DRC9	224	ubiquitous	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL35A	3,614
BDH1	1,297
DRC9	628

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL35A	P18077	194
DRC9	Q9H095	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BDH1	Q02338	87.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Utilization of Ketone Bodies	1	1427.5×	0.011	BDH1
Ketone body metabolism	1	951.7×	0.011	BDH1
Synthesis of Ketone Bodies	1	713.8×	0.011	BDH1
Peptide chain elongation	1	63.4×	0.026	RPL35A
Viral mRNA Translation	1	63.4×	0.026	RPL35A
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	62.8×	0.026	RPL35A
Selenocysteine synthesis	1	60.1×	0.026	RPL35A
Eukaryotic Translation Termination	1	60.1×	0.026	RPL35A
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	58.9×	0.026	RPL35A
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	58.9×	0.026	RPL35A
Mitochondrial protein degradation	1	57.1×	0.026	BDH1
Formation of a pool of free 40S subunits	1	56.0×	0.026	RPL35A
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	55.4×	0.026	RPL35A
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	1	53.4×	0.026	RPL35A
L13a-mediated translational silencing of Ceruloplasmin expression	1	50.5×	0.026	RPL35A
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.026	RPL35A
GTP hydrolysis and joining of the 60S ribosomal subunit	1	50.1×	0.026	RPL35A
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	48.8×	0.026	RPL35A
Regulation of expression of SLITs and ROBOs	1	34.6×	0.035	RPL35A
Major pathway of rRNA processing in the nucleolus and cytosol	1	30.9×	0.037	RPL35A
Metabolism of lipids	1	15.8×	0.068	BDH1
Metabolism of proteins	1	6.2×	0.162	BDH1
Metabolism	1	5.8×	0.165	BDH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium organization	1	200.6×	0.018	DRC9
sperm axoneme assembly	1	156.0×	0.018	DRC9
ribosomal large subunit biogenesis	1	147.8×	0.018	RPL35A
steroid metabolic process	1	112.3×	0.018	BDH1
cytoplasmic translation	1	61.7×	0.024	RPL35A
spermatid development	1	48.4×	0.024	DRC9
rRNA processing	1	47.2×	0.024	RPL35A
translation	1	34.2×	0.029	RPL35A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
RPL35A	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPL35A	1	4
BDH1	0	0
DRC9	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPL35A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RPL35A	90	Binding:90

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

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	RPL35A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RPL35A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BDH1, DRC9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BDH1	0	—
DRC9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.