USB1

Summary

USB1 (U6 snRNA biogenesis phosphodiesterase 1, HGNC:25792) is a protein-coding gene on chromosome 16q21, encoding U6 snRNA phosphodiesterase 1 (Q9BQ65). 3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate.

This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 79650 — RefSeq curated summary.

At a glance

• Gene–disease (curated): poikiloderma with neutropenia (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 503 total — 20 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 97
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_024598

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25792
Approved symbol	USB1
Name	U6 snRNA biogenesis phosphodiesterase 1
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13154, HVSL1, Mpn1
Ensembl gene	ENSG00000103005
Ensembl biotype	protein_coding
OMIM	613276
Entrez	79650

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 10 protein_coding, 6 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 TEC

ENST00000219281, ENST00000423271, ENST00000539737, ENST00000561568, ENST00000561743, ENST00000562534, ENST00000563149, ENST00000563207, ENST00000564387, ENST00000565151, ENST00000565662, ENST00000566082, ENST00000566292, ENST00000568848, ENST00000569252, ENST00000624720, ENST00000698444, ENST00000698445, ENST00000698446, ENST00000698447, ENST00000698510, ENST00000896281

RefSeq mRNA: 5 — MANE Select: NM_024598 NM_001195302, NM_001204911, NM_001330568, NM_001330569, NM_024598

CCDS: CCDS10791, CCDS55997, CCDS55998, CCDS81990, CCDS81991

Canonical transcript exons

ENST00000219281 — 7 exons

Exon	Start	End
ENSE00003462019	58014273	58014326
ENSE00003495565	58002479	58002645
ENSE00003562189	58018972	58019055
ENSE00003588036	58009929	58010112
ENSE00003654987	58017334	58017439
ENSE00003973682	58020141	58021618
ENSE00003973836	58001407	58001581

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 94.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1700 / max 438.5849, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154429	44.0151	1818
154428	0.9214	235
154427	0.2336	83

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.93	gold quality
leukocyte	CL:0000738	93.21	gold quality
monocyte	CL:0000576	93.17	gold quality
mononuclear cell	CL:0000842	93.08	gold quality
blood	UBERON:0000178	92.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.57	gold quality
lower esophagus	UBERON:0013473	91.54	gold quality
right adrenal gland	UBERON:0001233	91.50	gold quality
right adrenal gland cortex	UBERON:0035827	91.35	gold quality
left adrenal gland	UBERON:0001234	91.31	gold quality
left adrenal gland cortex	UBERON:0035825	90.96	gold quality
anterior cingulate cortex	UBERON:0009835	90.73	gold quality
cingulate cortex	UBERON:0003027	90.72	gold quality
islet of Langerhans	UBERON:0000006	90.64	gold quality
mucosa of transverse colon	UBERON:0004991	90.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.44	gold quality
right coronary artery	UBERON:0001625	90.42	gold quality
adrenal cortex	UBERON:0001235	90.25	gold quality
right lobe of thyroid gland	UBERON:0001119	90.21	gold quality
left lobe of thyroid gland	UBERON:0001120	90.19	gold quality
adrenal gland	UBERON:0002369	90.10	gold quality
heart left ventricle	UBERON:0002084	90.01	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.93	gold quality
stromal cell of endometrium	CL:0002255	89.88	gold quality
oocyte	CL:0000023	89.81	gold quality
apex of heart	UBERON:0002098	89.78	gold quality
cardiac ventricle	UBERON:0002082	89.61	gold quality
upper lobe of left lung	UBERON:0008952	89.43	gold quality
smooth muscle tissue	UBERON:0001135	89.36	gold quality
thoracic aorta	UBERON:0001515	89.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting USB1, 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-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 25)

• c16orf57 has a role in clericuzio-type poikiloderma with neutropenia (PMID:20004881)
• report on detailed clinical features of three siblings affected with Clericuzio poikiloderma with neutropenia syndrome, all carrying the same homozygous c.504-2A>Cmutation at the acceptor splice site of intron 4 of C16orf57 gene (PMID:20734427)
• findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. (PMID:20817924)
• Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia. (PMID:21271650)
• Mutations of the C16orf57 gene permit the unification of a distinct group of genetic polikilodermal dermatoses that can be diagnosed as congenital dyskeratosis, Rothmund-Thomson syndrome, poikiloderma-neutropenia. (PMID:21497268)
• We report three cases of poikiloderma with neutropenia whose clinical presentations, laboratory investigations, and C16orf57 mutation support the diagnosis. (PMID:21967010)
• characterization of 6 Poikiloderma with Neutropenia patients and mutational repertoire of the gene; detected 2 novel C16orf57 mutations, c.232C>T and c.265 2T>G and the reported c.179delC, c.531delA and c.693 1G>T mutations; bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function (PMID:22269211)
• Advanced bioinformatics predicted that C16orf57 encodes a phosphodiesterase whose putative catalytic activity is essential for its function in vivo (PMID:22899009)
• Recombinant hMpn1 is a 3’-to-5’ RNA exonuclease that removes uridines from U6 3’ ends, generating terminal 2’,3’ cyclic phosphates in vitro. (PMID:23022480)
• Data indicate that USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream. (PMID:23190533)
• Mpn1 associates with the NineTeen Complex, a multiprotein complex that is essential for the maintenance of spliceosome integrity and efficient splicing. [Review] (PMID:23684637)
• the link between Mpn1 and snRNA stability (PMID:26213367)
• USB1 genes from myelodysplastic and myelodysplastic/myeloproliferative neoplasms and AML had 3 unreported variants, 2 in USB1 5’UTR (c.-83G>T and c.-66A>G), 1 in IVS3 (c.450-68dupT) and 1 (<1%) in IVS4 (c.587+21A>G/rs200924980) were detected. (PMID:26306619)
• marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements. (PMID:27612988)
• this paper describes USB1 mutations characterized in four Moroccan patients out of three unrelated consanguinous families (PMID:28353165)
• Data indicate the enzymatic activities and structures of yeast and human U6 RNA processing enzyme Usb1. (PMID:28887445)
• A novel homozygous deletion of a 1-bp (c.161delC, p.P54RfsX60) in the C16orf57gene, was presumed to be causative of poikiloderma with neutropenia. The patient’s asymptomatic consanguineous parents were heterozygotes for this mutation. (PMID:29797650)
• Data show that U6 snRNA phosphodiesterase (Usb1) removes 3’ adenosines with 20-fold greater efficiency than uridines. (PMID:30215753)
• Here we investigate the molecular basis for the evolution of Usb1 CPDase activity. We examine the structure and function of Usb1 from Kluyveromyces marxianus, which shares 25 and 19% sequence identity to the S. cerevisiae and Homo sapiens orthologs of Usb1, respectively (PMID:31832688)
• Clinical Sequencing Solves a Diagnostic Dilemma by Identifying a Novel Pathogenic Variant in USB1 Gene Causing Poikiloderma with Neutropenia. (PMID:32936385)
• Clericuzio-type poikiloderma with neutropenia in a patient from India. (PMID:33111394)
• Kindler epidermolysis bullosa-like skin phenotype and downregulated basement membrane zone gene expression in poikiloderma with neutropenia and a homozygous USB1 mutation. (PMID:34004352)
• USB1 is a miRNA deadenylase that regulates hematopoietic development. (PMID:36862787)
• Chinese nontwin sisters suffer from poikiloderma with neutropenia harboring novel compound heterozygous USB1 gene mutations. (PMID:36938655)
• Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type. (PMID:37779259)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usb1	ENSDARG00000003841
mus_musculus	Usb1	ENSMUSG00000031792
rattus_norvegicus	Usb1	ENSRNOG00000013216
drosophila_melanogaster	CG16790	FBGN0037713

Protein

Protein identifiers

U6 snRNA phosphodiesterase 1 — Q9BQ65 (reviewed: Q9BQ65)

Alternative names: 3’-5’ RNA exonuclease USB1, Mutated in poikiloderma with neutropenia protein 1

All UniProt accessions (11): Q9BQ65, A0A8V8TLQ0, A0A8V8TLS7, A0A8V8TM89, A0A8V8TM93, A0A8V8TN78, A0A8V8TNL4, H3BN52, H3BNM8, H3BTS1, H3BTT8

UniProt curated annotations — full annotation on UniProt →

Function. 3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate. Participates in the U6 snRNA 3’ end processing that prevents U6 snRNA degradation. In addition also removes uridines from the 3’ end of U6atac snRNA and possibly the vault RNA VTRNA1-1.

Subunit / interactions. Interacts with PLRG1, CDC5L and PRPF19.

Subcellular location. Nucleus.

Disease relevance. Poikiloderma with neutropenia (PN) [MIM:604173] A genodermatosis characterized by poikiloderma, pachyonychia and chronic neutropenia. The disorder starts as a papular erythematous rash on the limbs during the first year of life. It gradually spreads centripetally and, as the papular rash resolves, hypo- and hyperpigmentation result, with development of telangiectasias. Another skin manifestation is pachyonychia, but alopecia and leukoplakia are distinctively absent. Patients have recurrent pneumonias that usually result in reactive airway disease and/or chronic cough. One of the most important extracutaneous symptoms is an increased susceptibility to infections, mainly affecting the respiratory system, primarily due to a chronic neutropenia and to neutrophil functional defects. Bone marrow abnormalities account for neutropenia and may evolve into myelodysplasia associated with the risk of leukemic transformation. Poikiloderma with neutropenia shows phenotypic overlap with Rothmund-Thomson syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. 3’-5’ RNA exonuclease activity is inhibited by a 3’ phosphate terminated RNA.

Similarity. Belongs to the 2H phosphoesterase superfamily. USB1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BQ65-1	1	yes
Q9BQ65-2	2
Q9BQ65-3	3

RefSeq proteins (5): NP_001182231, NP_001191840, NP_001317497, NP_001317498, NP_078874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027521	Usb1	Family

Pfam: PF09749

Catalyzed reactions (Rhea), 2 shown:

• a 3’-end uridylyl-uridine-RNA = a 3’-end 2’,3’-cyclophospho-uridine-RNA + uridine (RHEA:46052)
• a 3’-end uridylyl-adenosine-RNA = a 3’-end 2’,3’-cyclophospho-uridine-RNA + adenosine (RHEA:67896)

UniProt features (41 total): strand 9, mutagenesis site 8, helix 7, binding site 6, splice variant 2, sequence variant 2, sequence conflict 2, active site 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4H7W	X-RAY DIFFRACTION	1.1
6D30	X-RAY DIFFRACTION	1.17
6D2Z	X-RAY DIFFRACTION	1.18
6D31	X-RAY DIFFRACTION	1.2
5V1M	X-RAY DIFFRACTION	1.47

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQ65-F1	83.91	0.65

Functional residue map

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

Catalytic / active sites (2): 120 (proton acceptor); 208 (proton donor)

Ligand- & substrate-binding residues (6): 206–210; 120–122; 164; 202; 202; 204–210

Mutagenesis-validated functional residues (8):

Position	Phenotype
120	abolishes exoribonuclease activity. does not restore u6 snrna processing when expressed in deleted mpn1 yeast cells; whe
120	significantly decreases exonuclease activity.
122	significantly decreases exonuclease activity.
202	significantly decreases exonuclease activity.
208	abolishes exoribonuclease activity. does not rescue the molecular phenotype caused by usb1 depletion. does not restore u
208	loss of exonuclease activity.
210	significantly decreases exonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 354 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOMF_NUCLEASE_ACTIVITY, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_RNA_SPLICING, AACTTT_UNKNOWN, chr16q21, GOMF_EXONUCLEASE_ACTIVITY, ACEVEDO_LIVER_CANCER_UP, GOBP_SNRNA_PROCESSING, CHIBA_RESPONSE_TO_TSA, NUYTTEN_EZH2_TARGETS_DN, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, E2A_Q2

GO Biological Process (3): RNA splicing (GO:0008380), snRNA 3’-end processing (GO:0034472), U6 snRNA 3’-end processing (GO:0034477)

GO Molecular Function (6): 3’-5’-RNA exonuclease activity (GO:0000175), lyase activity (GO:0016829), poly(U)-specific exoribonuclease activity, producing 3’ uridine cyclic phosphate ends (GO:1990838), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), intercellular bridge (GO:0045171)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
cellular anatomical structure	2
RNA processing	1
snRNA processing	1
RNA 3’-end processing	1
snRNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
3’-5’-RNA exonuclease activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USB1	RECQL4	O94761	912
USB1	LSM8	O95777	690
USB1	NOP10	Q9NPE3	621
USB1	NHP2	Q9NX24	609
USB1	PRSS38	A1L453	597
USB1	WRAP53	Q9BUR4	593
USB1	TUT1	Q9H6E5	593
USB1	TINF2	Q9BSI4	574
USB1	LSM2	Q9Y333	574
USB1	DKC1	O60832	571
USB1	CTC1	Q2NKJ3	538
USB1	SNW1	Q13573	513
USB1	SART3	Q15020	511
USB1	YJU2	Q9BW85	505
USB1	RTEL1	Q9NZ71	478

IntAct

8 interactions, top by confidence:

A	B	Type	Score
USB1	AQR	psi-mi:“MI:0914”(association)	0.530
ECE1	USB1	psi-mi:“MI:0915”(physical association)	0.370
SMAD4	USB1	psi-mi:“MI:0915”(physical association)	0.370
USB1	PLRG1	psi-mi:“MI:0914”(association)	0.350
USB1	IGLL5	psi-mi:“MI:0914”(association)	0.350
purL	USB1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (96): PPIE (Affinity Capture-MS), XAB2 (Affinity Capture-MS), GPATCH1 (Affinity Capture-MS), DHX35 (Affinity Capture-MS), PRPF19 (Affinity Capture-MS), CRNKL1 (Affinity Capture-MS), BUD31 (Affinity Capture-MS), PLRG1 (Affinity Capture-MS), CDC5L (Affinity Capture-MS), AQR (Affinity Capture-MS), RBM22 (Affinity Capture-MS), WDR83 (Affinity Capture-MS), SNW1 (Affinity Capture-MS), CWF19L2 (Affinity Capture-MS), ISY1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L1SUL6, F1LQY6, O35465, O43379, O75293, O88910, O88954, P0C0T1, P21964, P22339, P41214, P50747, Q13368, Q13572, Q14318, Q16342, Q1HAQ0, Q28955, Q2T9Z1, Q3B7U9, Q3TFD2, Q3TMX7, Q496Y0, Q4AC99, Q5BIM1, Q5E9A5, Q5R812, Q5RA63, Q5SZD4, Q64311, Q6DC64, Q6P5G6, Q6PFY8, Q80YV4, Q8BNV1, Q8BYN3, Q8NFZ0, Q8R1C6, Q8R1T1, Q8TCU6

Diamond homologs: Q0II50, Q5I0I5, Q6DEF6, Q7ZYI9, Q91W78, Q9BQ65, Q9VHB3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	7
Uncertain significance	265
Likely benign	169
Benign	19

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1326260	NM_024598.3:c.334dup	Pathogenic
1338346	NM_024598.4(USB1):c.481del (p.Tyr161fs)	Pathogenic
1338579	NM_024598.4(USB1):c.206del (p.Gly69fs)	Pathogenic
156347	NM_024598.4(USB1):c.243G>A (p.Trp81Ter)	Pathogenic
18399	NM_024598.4(USB1):c.179del (p.Pro60fs)	Pathogenic
1924645	NM_024598.4(USB1):c.430del (p.Arg144fs)	Pathogenic
1941491	NM_024598.4(USB1):c.267T>G (p.Tyr89Ter)	Pathogenic
201	NM_024598.4(USB1):c.504-2A>C	Pathogenic
202	NM_024598.4(USB1):c.683_693+1del	Pathogenic
203	NM_024598.4(USB1):c.502A>G (p.Arg168Gly)	Pathogenic
4729837	NM_024598.4(USB1):c.193del (p.Thr65fs)	Pathogenic
496744	NM_024598.4(USB1):c.499del (p.Thr167fs)	Pathogenic
496745	NM_024598.4(USB1):c.531del (p.His179fs)	Pathogenic
496746	NM_024598.4(USB1):c.541C>T (p.Gln181Ter)	Pathogenic
496748	NM_024598.4(USB1):c.673C>T (p.Gln225Ter)	Pathogenic
496749	NM_024598.4(USB1):c.693+1G>T	Pathogenic
496750	NM_024598.4(USB1):c.176_177del (p.Gly59fs)	Pathogenic
496754	NM_024598.4(USB1):c.266-1G>A	Pathogenic
496757	NM_024598.4(USB1):c.415C>T (p.Gln139Ter)	Pathogenic
496761	NM_024598.4(USB1):c.489_492del (p.Asn163fs)	Pathogenic
1066183	NM_024598.4(USB1):c.418_449+5del	Likely pathogenic
1068250	NM_024598.4(USB1):c.99-2A>G	Likely pathogenic
1678064	NM_024598.4(USB1):c.450-1G>C	Likely pathogenic
2182373	NM_024598.4(USB1):c.503+1G>A	Likely pathogenic
496747	NM_024598.4(USB1):c.623A>G (p.His208Arg)	Likely pathogenic
559873	NM_024598.4(USB1):c.345del (p.Arg115_Met116insTer)	Likely pathogenic
800958	NM_024598.4(USB1):c.370T>C (p.Ser124Pro)	Likely pathogenic

SpliceAI

1422 predictions. Top by Δscore:

Variant	Effect	Δscore
16:58001529:GA:G	donor_gain	1.0000
16:58001530:A:G	donor_gain	1.0000
16:58001541:G:GT	donor_gain	1.0000
16:58001589:G:GG	donor_gain	1.0000
16:58001594:G:GT	donor_gain	1.0000
16:58002477:A:AG	acceptor_gain	1.0000
16:58002477:AGT:A	acceptor_gain	1.0000
16:58002478:G:GC	acceptor_gain	1.0000
16:58002478:GT:G	acceptor_gain	1.0000
16:58002478:GTG:G	acceptor_gain	1.0000
16:58002646:G:GG	donor_gain	1.0000
16:58012817:G:T	donor_gain	1.0000
16:58017329:CCCA:C	acceptor_loss	1.0000
16:58017331:CAGG:C	acceptor_loss	1.0000
16:58017332:A:AC	acceptor_loss	1.0000
16:58017332:A:AG	acceptor_gain	1.0000
16:58017332:AG:A	acceptor_gain	1.0000
16:58017333:G:GC	acceptor_gain	1.0000
16:58017333:GG:G	acceptor_gain	1.0000
16:58017333:GGA:G	acceptor_gain	1.0000
16:58017333:GGAC:G	acceptor_gain	1.0000
16:58017437:CAGG:C	donor_loss	1.0000
16:58017441:T:G	donor_loss	1.0000
16:58001584:GAGGA:G	donor_gain	0.9900
16:58001586:GGA:G	donor_gain	0.9900
16:58001587:GAG:G	donor_gain	0.9900
16:58001594:G:T	donor_gain	0.9900
16:58002474:T:A	acceptor_gain	0.9900
16:58002474:TGCAG:T	acceptor_gain	0.9900
16:58002475:GCAG:G	acceptor_gain	0.9900

AlphaMissense

1753 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:58017338:T:C	F170L	0.994
16:58017340:T:A	F170L	0.994
16:58017340:T:G	F170L	0.994
16:58018990:A:C	S210R	0.992
16:58018992:C:A	S210R	0.992
16:58018992:C:G	S210R	0.992
16:58010027:A:C	S122R	0.991
16:58010029:C:A	S122R	0.991
16:58010029:C:G	S122R	0.991
16:58017416:T:C	F196L	0.988
16:58017418:C:A	F196L	0.988
16:58017418:C:G	F196L	0.988
16:58018984:C:G	H208D	0.987
16:58002623:G:C	W81C	0.986
16:58002623:G:T	W81C	0.986
16:58002621:T:A	W81R	0.983
16:58002621:T:C	W81R	0.983
16:58017431:T:C	F201L	0.982
16:58017433:C:A	F201L	0.982
16:58017433:C:G	F201L	0.982
16:58002634:T:A	V85D	0.981
16:58017344:G:T	G172W	0.980
16:58017345:G:A	G172E	0.980
16:58002600:T:C	F74L	0.979
16:58002602:C:A	F74L	0.979
16:58002602:C:G	F74L	0.979
16:58017339:T:C	F170S	0.979
16:58018981:T:C	F207L	0.979
16:58018983:C:A	F207L	0.979
16:58018983:C:G	F207L	0.979

dbSNP variants (sampled 300 via entrez): RS1000081441 (16:58022031 G>C), RS1000234762 (16:57999466 C>T), RS1000343835 (16:58004754 T>C), RS1000461198 (16:58001461 C>A,G,T), RS1000498937 (16:58019590 G>A), RS1000669430 (16:58007824 T>A), RS1000976965 (16:58014699 C>A), RS1001102058 (16:58000736 C>T), RS1001204734 (16:58006224 T>C), RS1001228807 (16:58007984 A>G), RS1001284267 (16:58021330 C>T), RS1001340534 (16:58006040 T>C), RS1001638130 (16:58000546 C>G), RS1001894886 (16:58012106 G>A), RS1001950136 (16:58007725 C>T)

Disease associations

OMIM: gene MIM:613276 | disease phenotypes: MIM:604173

GenCC curated gene-disease

Disease	Classification	Inheritance
poikiloderma with neutropenia	Definitive	Autosomal recessive
dyskeratosis congenita	Supportive	Autosomal dominant

Mondo (2): poikiloderma with neutropenia (MONDO:0011405), dyskeratosis congenita (MONDO:0015780)

Orphanet (1): Poikiloderma with neutropenia (Orphanet:221046)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000430	Underdeveloped nasal alae
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000509	Conjunctivitis
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000579	Nasolacrimal duct obstruction
HP:0000600	Abnormality of the pharynx
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000704	Periodontitis
HP:0000819	Diabetes mellitus
HP:0000939	Osteoporosis
HP:0000962	Hyperkeratosis
HP:0000969	Edema
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
2-palmitoylglycerol	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Diazinon	increases methylation	1
Diuron	decreases expression	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tunicamycin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4VQ	PN1-iPSC	Induced pluripotent stem cell	Female
CVCL_A4VR	PN2-iPSC	Induced pluripotent stem cell	Female
CVCL_B2KG	Abcam HeLa USB1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts