DCLRE1B

Summary

DCLRE1B (DNA cross-link repair 1B, HGNC:17641) is a protein-coding gene on chromosome 1p13.2, encoding 5’ exonuclease Apollo (Q9H816). 5’-3’ exonuclease that plays a central role in telomere maintenance and protection during S-phase. It is a selective cancer dependency (DepMap: 73.8% of cell lines).

DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1B is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000 [PubMed 10848582]).

Source: NCBI Gene 64858 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dyskeratosis congenita, autosomal recessive 8 (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 176 total — 5 pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 73.8% of screened cell lines
• MANE Select transcript: NM_022836

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17641
Approved symbol	DCLRE1B
Name	DNA cross-link repair 1B
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	SNM1B, FLJ12810, FLJ13998, APOLLO
Ensembl gene	ENSG00000118655
Ensembl biotype	protein_coding
OMIM	609683
Entrez	64858

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000466480, ENST00000648795, ENST00000650450, ENST00000650596, ENST00000697125, ENST00000697126, ENST00000935642, ENST00000935643, ENST00000970516

RefSeq mRNA: 5 — MANE Select: NM_022836 NM_001319946, NM_001319947, NM_001363690, NM_001363691, NM_022836

CCDS: CCDS866

Canonical transcript exons

ENST00000650450 — 4 exons

Exon	Start	End
ENSE00000913490	113906996	113907161
ENSE00001450343	113911131	113914086
ENSE00003618653	113908009	113908191
ENSE00003836301	113905326	113905775

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 87.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3779 / max 226.6489, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4728	13.9863	1719
4729	5.0050	1353
4727	0.3865	171

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	87.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.00	gold quality
oocyte	CL:0000023	84.42	gold quality
ganglionic eminence	UBERON:0004023	82.30	gold quality
ventricular zone	UBERON:0003053	81.92	gold quality
monocyte	CL:0000576	79.50	gold quality
leukocyte	CL:0000738	79.46	gold quality
mononuclear cell	CL:0000842	79.39	gold quality
cortical plate	UBERON:0005343	78.71	gold quality
skin of hip	UBERON:0001554	78.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.35	gold quality
granulocyte	CL:0000094	77.16	gold quality
bone marrow	UBERON:0002371	76.66	gold quality
embryo	UBERON:0000922	76.45	gold quality
trabecular bone tissue	UBERON:0002483	75.59	gold quality
stromal cell of endometrium	CL:0002255	75.36	gold quality
palpebral conjunctiva	UBERON:0001812	75.14	gold quality
popliteal artery	UBERON:0002250	74.80	gold quality
tibial artery	UBERON:0007610	74.79	gold quality
buccal mucosa cell	CL:0002336	74.18	silver quality
bone marrow cell	CL:0002092	73.80	gold quality
islet of Langerhans	UBERON:0000006	73.53	gold quality
rectum	UBERON:0001052	72.99	gold quality
sperm	CL:0000019	72.97	gold quality
lymph node	UBERON:0000029	72.57	gold quality
blood	UBERON:0000178	72.56	gold quality
amniotic fluid	UBERON:0000173	72.38	gold quality
aorta	UBERON:0000947	72.19	gold quality
right coronary artery	UBERON:0001625	72.11	gold quality
smooth muscle tissue	UBERON:0001135	71.91	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting DCLRE1B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548O-3P	99.74	69.30	2228

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 73.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair (PMID:15467758)
• the C terminus of Snm1B was shown to interact with the TRF homology domain of TRF2 indicating that Snm1B is likely recruited to the telomere via interaction with the double-stranded telomere-binding protein TRF2 (PMID:16606622)
• SNM1B (Apollo) protein exhibits a 5’-to-3’ DNA exonuclease activity and functions together with TRF2 to protect telomeres from damage and fusion. (PMID:16730175)
• SNM1B (Apollo) is an Artemis-like nuclease that is required for the protection of telomeres during or after their replication. [Apollo] (PMID:16730176)
• observations suggest an important role for hSNM1B in the response to ionizing radiation damage, a role that may be, in part, upstream of the central player in maintenance of genome integrity, ATM (PMID:18468965)
• Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein. (PMID:18469862)
• The protein hSnm1B is stabilized when bound to the telomere-binding protein TRF2 (PMID:18593705)
• Results suggest that SNM1B/Apollo and Astrin function together to enforce the prophase checkpoint in response to spindle stress. (PMID:19197158)
• DCLRE1B protein binds to a C-terminal fragment of HSP72 Heat-Shock Proteins, known to contain the substrate binding domain. (PMID:19411856)
• TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. (PMID:20655466)
• SNM1B functions epistatically to the central Fanconi anemia factor, FANCD2, in cellular survival after interstrand crosslinks damage and homology-directed repair of DNA double-strand breaks (PMID:21478198)
• differences in the substrate selectivities of SNM1A and SNM1B are likely to be relevant to their in vivo roles (PMID:22692201)
• The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4. (PMID:22907656)
• the N-terminal region of Snm1B forms a complex containing PSF2 and Mus81, while the C-terminal region is important for PSF2-mediated chromatin association. (PMID:23189151)
• The SNM1B/APOLLO DNA nuclease functions in resolution of replication stress and maintenance of common fragile site stability. (PMID:23863462)
• Different charge distributions along the DNA binding groove may account for the drastic difference in processivity and DNA digestion efficiency, including that of damaged substrates, between SNM1A and SNM1B. (PMID:26582912)
• A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family. (PMID:34387694)
• Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition. (PMID:34387696)
• DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer. (PMID:37936074)
• DNA-PK controls Apollo’s access to leading-end telomeres. (PMID:38407308)
• DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection. (PMID:38430974)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dclre1b	ENSDARG00000068833
mus_musculus	Dclre1b	ENSMUSG00000027845
rattus_norvegicus	Dclre1b	ENSRNOG00000019367
caenorhabditis_elegans		WBGENE00007065
caenorhabditis_elegans		WBGENE00010195
caenorhabditis_elegans	mrt-1	WBGENE00045237

Paralogs (2): DCLRE1C (ENSG00000152457), DCLRE1A (ENSG00000198924)

Protein

Protein identifiers

5’ exonuclease Apollo — Q9H816 (reviewed: Q9H816)

Alternative names: Beta-lactamase DCLRE1B, DNA cross-link repair 1B protein, SNM1 homolog B

All UniProt accessions (3): A0A3B3IT16, A0A3B3ITQ0, Q9H816

UniProt curated annotations — full annotation on UniProt →

Function. 5’-3’ exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3’ single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint. Possesses beta-lactamase activity, catalyzing the hydrolysis of penicillin G and nitrocefin. Exhibits no activity towards other beta-lactam antibiotic classes including cephalosporins (cefotaxime) and carbapenems (imipenem).

Subunit / interactions. Interacts with TERF2; the interaction is direct. Interacts with MUS81, MRE11 and FANCD2. Interacts with HSPA2, HSPA8 and HSPA14. Interacts with SPAG5.

Subcellular location. Chromosome. Telomere. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Ubiquitinated, leading to its degradation. Interaction with TERF2 protects it from ubiquitination.

Disease relevance. Dyskeratosis congenita, autosomal recessive, 8 (DKCB8) [MIM:620133] A form of dyskeratosis congenita, a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. Additional DKCB8 features include microcephaly, intrauterine growth retardation, and developmental anomalies in some patients. DKCB8 patients exhibit normal global telemore length, although there is evidence of telomere instability. The disease is caused by variants affecting the gene represented in this entry. In addition to missense and stop-gain variants, an aberrant splice variant of DCLRE1B, designated Apollo-Delta, has been found in a patient with severe dyskeratosis congenita and features of Hoyeraal-Hreidarsson syndrome. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome.

Activity regulation. Beta-lactamase activity is inhibited by sulbactam.

Domain organisation. The TBM domain mediates interaction with TERF2.

Miscellaneous. Was named ‘Apollo’ in reference to the twin brother of ‘Artemis’ in Greek mythology. Artemis/DCLRE1C is a related nuclease.

Similarity. Belongs to the DNA repair metallo-beta-lactamase (DRMBL) family.

RefSeq proteins (5): NP_001306875, NP_001306876, NP_001350619, NP_001350620, NP_073747* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011084	DRMBL	Domain
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily

Pfam: PF07522

Catalyzed reactions (Rhea), 1 shown:

• a beta-lactam + H2O = a substituted beta-amino acid (RHEA:20401)

UniProt features (59 total): strand 19, helix 17, sequence variant 8, mutagenesis site 7, region of interest 2, turn 2, chain 1, sequence conflict 1, short sequence motif 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7A1F	X-RAY DIFFRACTION	1.8
5AHO	X-RAY DIFFRACTION	2.16
3BUA	X-RAY DIFFRACTION	2.5
7B9B	X-RAY DIFFRACTION	2.8
7B2X	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H816-F1	74.95	0.58

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 333

Mutagenesis-validated functional residues (7):

Position	Phenotype
14	in apm3; abolishes exonuclease activity and function on telomere maintenance. impairs interaction with spag5.
33	in apm1; abolishes exonuclease activity and function on telomere maintenance; when associated with n-35.
35	in apm2; abolishes exonuclease activity and function on telomere maintenance. in apm1; abolishes exonuclease activity an
276	slightly affects interaction with spag5.
504	abolishes interaction with terf2.
506	abolishes interaction with terf2.
508	abolishes interaction with terf2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6783310	Fanconi Anemia Pathway

MSigDB gene sets: 225 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_TELOMERE_CAPPING, FISCHER_G1_S_CELL_CYCLE, GOMF_NUCLEASE_ACTIVITY, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES, GOCC_MICROTUBULE_ORGANIZING_CENTER, CAGCAGG_MIR370, BILD_E2F3_ONCOGENIC_SIGNATURE, GOCC_CENTROSOME, GOBP_DNA_STRAND_ELONGATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, FISCHER_DREAM_TARGETS

GO Biological Process (10): telomere maintenance (GO:0000723), double-strand break repair via nonhomologous end joining (GO:0006303), telomere maintenance via telomere lengthening (GO:0010833), telomere capping (GO:0016233), telomeric loop formation (GO:0031627), protection from non-homologous end joining at telomere (GO:0031848), telomeric 3’ overhang formation (GO:0031860), interstrand cross-link repair (GO:0036297), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (10): damaged DNA binding (GO:0003684), 5’-3’ exonuclease activity (GO:0008409), beta-lactamase activity (GO:0008800), 5’-3’ DNA exonuclease activity (GO:0035312), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), nuclear body (GO:0016604), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
telomere maintenance	3
intracellular membraneless organelle	3
DNA metabolic process	2
telomere capping	2
binding	2
cellular anatomical structure	2
telomere organization	1
double-strand break repair	1
telomere maintenance in response to DNA damage	1
DNA strand elongation	1
DNA repair	1
DNA damage response	1
cellular response to stress	1
DNA binding	1
exonuclease activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in cyclic amides	1
5’-3’ exonuclease activity	1
DNA exonuclease activity, producing 5’-phosphomonoesters	1
identical protein binding	1
protein dimerization activity	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
nucleoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1397 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCLRE1B	TERF2	Q15554	968
DCLRE1B	TINF2	Q9BSI4	896
DCLRE1B	TERF1	P54274	882
DCLRE1B	SLX4	Q8IY92	851
DCLRE1B	TERF2IP	Q9NYB0	755
DCLRE1B	POT1	Q9NUX5	750
DCLRE1B	WRN	Q14191	698
DCLRE1B	MUS81	Q96NY9	680
DCLRE1B	TNKS	O95271	655
DCLRE1B	PRKDC	P78527	653
DCLRE1B	EXO1	Q9UQ84	634
DCLRE1B	SLX1A	Q9BQ83	612
DCLRE1B	CPSF3	Q9UKF6	599
DCLRE1B	ERCC1	P07992	587
DCLRE1B	FANCM	Q8IYD8	587

IntAct

67 interactions, top by confidence:

A	B	Type	Score
DCLRE1B	TERF2	psi-mi:“MI:0915”(physical association)	0.920
TERF2	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.920
TERF2	DCLRE1B	psi-mi:“MI:0403”(colocalization)	0.920
DCLRE1B	TERF2	psi-mi:“MI:0403”(colocalization)	0.920
DCLRE1B	TERF2	psi-mi:“MI:0914”(association)	0.920
S100B	S100A4	psi-mi:“MI:0914”(association)	0.870
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
NOXA1	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	APOE	psi-mi:“MI:0915”(physical association)	0.560
COMT	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	DNM2	psi-mi:“MI:0915”(physical association)	0.560
ELAVL4	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560
PSEN1	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	WFS1	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	NDRG1	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	TDP1	psi-mi:“MI:0915”(physical association)	0.560
DCLRE1B	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	DCLRE1B	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (64): HSPD1 (Affinity Capture-MS), PRKDC (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF2 (Affinity Capture-MS), POT1 (Affinity Capture-MS), TINF2 (Affinity Capture-MS), TERF2IP (Affinity Capture-MS), FNBP1L (Affinity Capture-MS), KANSL2 (Affinity Capture-MS), SLC39A10 (Affinity Capture-MS), DCLRE1B (Affinity Capture-MS), DCLRE1B (Affinity Capture-MS), DCLRE1B (Affinity Capture-MS), DCLRE1B (Affinity Capture-MS), DCLRE1B (Affinity Capture-MS)

ESM2 similar proteins: A0JPN4, A2AKB4, A2APT9, A4Q9E8, A4Q9F6, A6NNM8, A6QQJ8, A8CVX7, B2GUW6, D2H8V8, O88866, O94761, P48778, Q14154, Q2YDK1, Q3TYG6, Q49AM3, Q4KLY6, Q4QQS0, Q4R747, Q5D1E7, Q5D1E8, Q5NC05, Q5RA67, Q5REE2, Q5SXM2, Q60953, Q6ZQM0, Q6ZUX3, Q6ZW76, Q75NR7, Q7TSG2, Q8BIY3, Q8BP86, Q8C7W7, Q8IX06, Q8N841, Q8R2S1, Q8VCU0, Q8WTP8

Diamond homologs: B0V2S2, D2H8V8, F4HPZ9, Q38961, Q4KLY6, Q55470, Q5QJC3, Q5QJC4, Q5R6Z9, Q5XIX3, Q6PJP8, Q86KS1, Q8C7W7, Q8K4J0, Q96SD1, Q9H816, Q9JIC3, P30620, Q5QJC2, Q5RGE5, A1RTK4, A1RY72, A2BJX6, A3DP49, A3MS62, A4WH24, A4YD25, A8AB20, A8MDU6, B1L3V2, B1YA52, C0QSL7, C3MJ14, C3MYD2, C3MZR1, C3N834, C3NF77, C4KIZ2, D2CJS7, O67398

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Meiotic synapsis	5	29.4×	2e-05
Cell Cycle	5	7.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

176 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	112
Likely benign	40
Benign	16

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1801220	NM_022836.4(DCLRE1B):c.426A>T (p.Leu142Phe)	Pathogenic
1801221	NM_022836.4(DCLRE1B):c.364C>T (p.Arg122Ter)	Pathogenic
1801222	NM_022836.4(DCLRE1B):c.425T>C (p.Leu142Ser)	Pathogenic
2498208	NM_022836.4(DCLRE1B):c.248A>G (p.Asp83Gly)	Pathogenic
2498209	NM_022836.4(DCLRE1B):c.807C>T (p.His269=)	Pathogenic

SpliceAI

515 predictions. Top by Δscore:

Variant	Effect	Δscore
1:113904601:ATAC:A	donor_loss	1.0000
1:113904602:TACC:T	donor_loss	1.0000
1:113904604:C:CA	donor_loss	1.0000
1:113904604:CCTAA:C	donor_gain	1.0000
1:113904605:CTAAT:C	donor_gain	1.0000
1:113904606:TAATC:T	donor_gain	1.0000
1:113904607:A:AC	donor_gain	1.0000
1:113904607:AAT:A	donor_gain	1.0000
1:113904607:AATCA:A	donor_gain	1.0000
1:113904612:CTCG:C	donor_gain	1.0000
1:113905771:TACAG:T	donor_loss	1.0000
1:113905772:ACAGG:A	donor_loss	1.0000
1:113905773:CAG:C	donor_loss	1.0000
1:113905774:AGG:A	donor_loss	1.0000
1:113905775:GGTA:G	donor_loss	1.0000
1:113905776:GTATG:G	donor_loss	1.0000
1:113905777:T:A	donor_loss	1.0000
1:113908187:GATTG:G	donor_gain	1.0000
1:113908188:A:G	donor_gain	1.0000
1:113908188:ATTGG:A	donor_loss	1.0000
1:113908189:TTGGT:T	donor_loss	1.0000
1:113908191:GGTG:G	donor_loss	1.0000
1:113908192:G:T	donor_loss	1.0000
1:113908193:T:A	donor_loss	1.0000
1:113911110:A:AG	acceptor_gain	1.0000
1:113911111:A:G	acceptor_gain	1.0000
1:113911113:A:AG	acceptor_gain	1.0000
1:113911113:ACATT:A	acceptor_gain	1.0000
1:113911115:A:AG	acceptor_gain	1.0000
1:113911115:ATT:A	acceptor_gain	1.0000

AlphaMissense

3479 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:113905632:T:A	W16R	0.993
1:113905632:T:C	W16R	0.993
1:113905675:C:T	S30F	0.992
1:113905716:T:A	W44R	0.992
1:113905716:T:C	W44R	0.992
1:113905736:C:G	C50W	0.991
1:113907123:T:C	F106S	0.991
1:113907129:T:C	F108S	0.991
1:113907081:T:A	V92E	0.990
1:113905669:T:C	F28S	0.989
1:113908080:T:G	Y143D	0.989
1:113905626:G:C	D14H	0.988
1:113911437:T:C	L282P	0.987
1:113905627:A:T	D14V	0.986
1:113905665:T:C	F27L	0.986
1:113905667:C:A	F27L	0.986
1:113905667:C:G	F27L	0.986
1:113907126:T:C	L107P	0.986
1:113911422:C:T	S277F	0.986
1:113905675:C:A	S30Y	0.985
1:113905718:G:C	W44C	0.985
1:113905718:G:T	W44C	0.985
1:113908084:T:C	L144P	0.985
1:113907134:G:A	G110R	0.984
1:113907134:G:C	G110R	0.984
1:113907153:T:C	L116P	0.984
1:113907114:C:T	S103F	0.983
1:113908012:A:T	D120V	0.983
1:113911250:T:C	F220L	0.983
1:113911252:C:A	F220L	0.983

dbSNP variants (sampled 300 via entrez): RS1000183998 (1:113913617 A>G), RS1000241143 (1:113907237 T>A,C,G), RS1000564610 (1:113912575 G>T), RS1000566827 (1:113906142 C>T), RS1000639581 (1:113913795 G>A,T), RS1000671626 (1:113906697 G>T), RS1000759357 (1:113904235 T>G), RS1000866615 (1:113910479 T>G), RS1001243804 (1:113908470 C>G,T), RS1001292997 (1:113908735 A>G,T), RS1001318879 (1:113910180 C>G,T), RS1001550726 (1:113905354 C>G,T), RS1001695920 (1:113911558 T>C,G), RS1001935252 (1:113903733 TAA>T), RS1002095088 (1:113909724 C>A,T)

Disease associations

OMIM: gene MIM:609683 | disease phenotypes: MIM:620133, MIM:614066, MIM:227645

GenCC curated gene-disease

Disease	Classification	Inheritance
dyskeratosis congenita, autosomal recessive 8	Strong	Autosomal recessive

Mondo (4): Hoyeraal-Hreidarsson syndrome (MONDO:0018045), dyskeratosis congenita, autosomal recessive 8 (MONDO:0859319), hereditary spastic paraplegia 47 (MONDO:0013551), Fanconi anemia complementation group C (MONDO:0009213)

Orphanet (3): Hoyeraal-Hreidarsson syndrome (Orphanet:3322), Severe intellectual disability and progressive spastic paraplegia (Orphanet:280763), Fanconi anemia (Orphanet:84)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000601	Hypotelorism
HP:0000750	Delayed speech and language development
HP:0000967	Petechiae
HP:0001272	Cerebellar atrophy
HP:0001511	Intrauterine growth retardation
HP:0001622	Premature birth
HP:0001876	Pancytopenia
HP:0002037	Inflammation of the large intestine
HP:0002043	Esophageal stricture
HP:0002209	Sparse scalp hair
HP:0002721	Immunodeficiency
HP:0002745	Oral leukoplakia
HP:0003221	Chromosomal breakage induced by crosslinking agents
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0005528	Bone marrow hypocellularity
HP:0008404	Nail dystrophy
HP:0010976	Decreased total B cell count
HP:0033256	Pancolitis
HP:0040218	Reduced total natural killer cell count

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001729_13	Crohn’s disease	2.000000e-15
GCST001937_47	Breast cancer	2.000000e-08
GCST004132_97	Crohn’s disease	4.000000e-06
GCST004866_5	Alopecia areata	7.000000e-07
GCST004988_218	Breast cancer	5.000000e-11
GCST006697_12	Parental longevity (combined parental attained age, Martingale residuals)	6.000000e-06
GCST010866_17	Coronary artery disease	4.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007796	parental longevity

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536068	Hoyeraal Hreidarsson syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105944 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	4
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
N(4)-hydroxycytidine	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arecoline	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cannabidiol	decreases expression	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Oxygen	decreases expression	1
Rifampin	decreases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4027952	Binding	Inhibition of human DCLRE1B	In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. — J Med Chem

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia