TSEN54

Summary

TSEN54 (tRNA splicing endonuclease subunit 54, HGNC:27561) is a protein-coding gene on chromosome 17q25.1, encoding tRNA-splicing endonuclease subunit Sen54 (Q7Z6J9). Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It is a common-essential gene (DepMap: required in 95.0% of cancer cell lines).

This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.

Source: NCBI Gene 283989 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 5 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 669 total — 49 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 74
• Cancer dependency (DepMap): dependent in 95.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_207346

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27561
Approved symbol	TSEN54
Name	tRNA splicing endonuclease subunit 54
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	SEN54, SEN54L
Ensembl gene	ENSG00000182173
Ensembl biotype	protein_coding
OMIM	608755
Entrez	283989

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 15 protein_coding, 10 retained_intron, 6 nonsense_mediated_decay

ENST00000333213, ENST00000434205, ENST00000545228, ENST00000577197, ENST00000578415, ENST00000579449, ENST00000580013, ENST00000583173, ENST00000583454, ENST00000583634, ENST00000583818, ENST00000679370, ENST00000679429, ENST00000679443, ENST00000679782, ENST00000679919, ENST00000679928, ENST00000680528, ENST00000680999, ENST00000681282, ENST00000884601, ENST00000884602, ENST00000884603, ENST00000884604, ENST00000915432, ENST00000915433, ENST00000915434, ENST00000915435, ENST00000915436, ENST00000947128, ENST00000947129

RefSeq mRNA: 1 — MANE Select: NM_207346 NM_207346

CCDS: CCDS11724

Canonical transcript exons

ENST00000333213 — 11 exons

Exon	Start	End
ENSE00001333626	75521705	75522333
ENSE00001333638	75524262	75524735
ENSE00002689065	75516528	75516616
ENSE00003487264	75523663	75523779
ENSE00003516344	75517009	75517072
ENSE00003555375	75523275	75523335
ENSE00003587978	75521409	75521510
ENSE00003654714	75517557	75517655
ENSE00003684573	75516746	75516910
ENSE00003688977	75517161	75517244
ENSE00003791400	75518995	75519047

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 97.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.9376 / max 72.3803, expressed in 1667 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162730	8.7647	1661
162732	0.1385	66
162731	0.0345	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.54	gold quality
right uterine tube	UBERON:0001302	97.42	gold quality
cerebellar hemisphere	UBERON:0002245	97.17	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.12	gold quality
upper arm skin	UBERON:0004263	97.06	silver quality
cerebellar cortex	UBERON:0002129	97.01	gold quality
lower esophagus mucosa	UBERON:0035834	96.58	gold quality
cerebellum	UBERON:0002037	96.50	gold quality
mucosa of transverse colon	UBERON:0004991	95.76	gold quality
body of pancreas	UBERON:0001150	95.44	gold quality
metanephros cortex	UBERON:0010533	95.40	gold quality
kidney epithelium	UBERON:0004819	95.22	silver quality
pylorus	UBERON:0001166	95.05	gold quality
cardia of stomach	UBERON:0001162	95.02	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.36	gold quality
right lobe of thyroid gland	UBERON:0001119	94.04	gold quality
pharyngeal mucosa	UBERON:0000355	94.01	gold quality
adenohypophysis	UBERON:0002196	93.74	gold quality
body of tongue	UBERON:0011876	93.61	silver quality
inferior vagus X ganglion	UBERON:0005363	93.55	gold quality
gall bladder	UBERON:0002110	93.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.48	gold quality
pituitary gland	UBERON:0000007	93.47	gold quality
trachea	UBERON:0003126	93.46	gold quality
left lobe of thyroid gland	UBERON:0001120	93.44	gold quality
spleen	UBERON:0002106	93.40	gold quality
tongue	UBERON:0001723	93.39	silver quality
left ventricle myocardium	UBERON:0006566	93.38	gold quality
superior surface of tongue	UBERON:0007371	93.29	silver quality
esophagus mucosa	UBERON:0002469	93.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting TSEN54, 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-4682	100.00	68.89	1258
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-4732-3P	97.15	65.45	881
HSA-MIR-4484	96.35	64.08	382
HSA-MIR-4281	92.91	63.60	271

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 95.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. (PMID:18711368)
• We confirm that the common p.A307S mutation in TSEN54 is responsible for most of the patients with a PCH2 phenotype. (PMID:20956791)
• The results demonistrated that not all cases of clinically defined pontocerebellar hypoplasia-4 result from mutations in TSEN54. (PMID:21383226)
• TSEN54 mutation causes a severe form of pontocerebellar hypoplasia type 1 in a family. (PMID:21468723)
• A novel heterozygous mutation was found in the TSEN54 gene by c.254A > T(+) (p.E85V), which may be a new subtype of hereditary ataxia (PMID:24938831)
• TSEN54 gene-related pontocerebellar hypoplasia type 2 presented with exaggerated startle response in cousins. (PMID:26701950)
• A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family. (PMID:32697043)
• Comprehensive analysis reveals TSEN54 as a robust prognosis biomarker and promising immune-related therapeutic target for hepatocellular carcinoma. (PMID:37059591)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsen54	ENSDARG00000036844
mus_musculus	Tsen54	ENSMUSG00000020781
rattus_norvegicus	Tsen54	ENSRNOG00000004598
drosophila_melanogaster	Tsen54	FBGN0036266
caenorhabditis_elegans		WBGENE00018680

Protein

Protein identifiers

tRNA-splicing endonuclease subunit Sen54 — Q7Z6J9 (reviewed: Q7Z6J9)

Alternative names: SEN54 homolog, tRNA-intron endonuclease Sen54

All UniProt accessions (9): Q7Z6J9, A0A7P0TA59, A0A7P0Z413, A0A7P0Z4H0, A0A7P0Z4K6, E7EN92, J3KRC5, J3QLM6, J9JIH8

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It cleaves pre-tRNA at the 5’ and 3’ splice sites to release the intron. The products are an intron and two tRNA half-molecules bearing 2’,3’ cyclic phosphate and 5’-OH termini. There are no conserved sequences at the splice sites, but the intron is invariably located at the same site in the gene, placing the splice sites an invariant distance from the constant structural features of the tRNA body. The tRNA splicing endonuclease is also involved in mRNA processing via its association with pre-mRNA 3’-end processing factors, establishing a link between pre-tRNA splicing and pre-mRNA 3’-end formation, suggesting that the endonuclease subunits function in multiple RNA-processing events.

Subunit / interactions. tRNA splicing endonuclease is a heterotetramer composed of TSEN2, TSEN15, TSEN34/LENG5 and TSEN54. tRNA splicing endonuclease complex also contains proteins of the pre-mRNA 3’-end processing machinery such as CLP1, CPSF1, CPSF4 and CSTF2. Also belongs to a complex containing isoform 2 of SEN2.

Subcellular location. Nucleus. Nucleolus.

Disease relevance. Pontocerebellar hypoplasia 4 (PCH4) [MIM:225753] A disorder characterized by an abnormally small cerebellum and brainstem, severe neonatal encephalopathy, microcephaly, myoclonus and muscular hypertonia. There is a severe inferior olivary and pontine neuronal loss and a diffuse white matter gliosis. The disease is caused by variants affecting the gene represented in this entry. Pontocerebellar hypoplasia 2A (PCH2A) [MIM:277470] A disorder characterized by an abnormally small cerebellum and brainstem, and progressive microcephaly from birth combined with extrapyramidal dyskinesia. Severe chorea occurs and epilepsy is frequent. There are no signs of spinal cord anterior horn cells degeneration. The disease is caused by variants affecting the gene represented in this entry. Pontocerebellar hypoplasia 5 (PCH5) [MIM:610204] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum. Brain MRI shows an abnormally small cerebellum and brainstem, decreased cerebral white matter, and a thin corpus callosum. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SEN54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z6J9-1	1	yes
Q7Z6J9-2	2

RefSeq proteins (1): NP_997229* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024336	tRNA_splic_suSen54_N	Domain
IPR024337	tRNA_splic_suSen54	Family

Pfam: PF12928

Enzyme classification (BRENDA):

• EC 4.6.1.16 — tRNA-intron lyase (BRENDA: 22 organisms, 86 substrates, 10 inhibitors, 1 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PRETRNA	0.0003	1

UniProt features (56 total): strand 20, helix 12, sequence variant 10, modified residue 5, turn 3, region of interest 2, splice variant 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8HMZ	ELECTRON MICROSCOPY	2.9
8HMY	ELECTRON MICROSCOPY	2.94
7ZRZ	ELECTRON MICROSCOPY	3.09
8ISS	ELECTRON MICROSCOPY	3.19
7UXA	ELECTRON MICROSCOPY	3.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z6J9-F1	73.60	0.27

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 (5): 1, 178, 180, 267, 316

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 268 (showing top): CREL_01, GCANCTGNY_MYOD_Q6, SP3_Q3, GOBP_TRNA_METABOLIC_PROCESS, AAGCCAT_MIR135A_MIR135B, CAGCTG_AP4_Q5, PATIL_LIVER_CANCER, GTGCCTT_MIR506, MYOD_01, GOBP_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION, GOBP_RNA_SPLICING, MYOD_Q6, AACTTT_UNKNOWN, RYTTCCTG_ETS2_B, VDR_Q3

GO Biological Process (4): tRNA-type intron splice site recognition and cleavage (GO:0000379), tRNA splicing, via endonucleolytic cleavage and ligation (GO:0006388), mRNA processing (GO:0006397), tRNA processing (GO:0008033)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): tRNA-intron endonuclease complex (GO:0000214), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	3
nuclear lumen	2
tRNA splicing, via endonucleolytic cleavage and ligation	1
RNA splicing, via endonucleolytic cleavage and ligation	1
tRNA processing	1
mRNA metabolic process	1
tRNA metabolic process	1
binding	1
nuclear protein-containing complex	1
endoribonuclease complex	1
cellular anatomical structure	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSEN54	TSEN2	Q8NCE0	999
TSEN54	TSEN15	Q8WW01	999
TSEN54	TSEN34	Q9BSV6	999
TSEN54	RARS2	Q5T160	952
TSEN54	VRK1	Q99986	776
TSEN54	TOE1	Q96GM8	674
TSEN54	EXOSC3	Q9NQT5	672
TSEN54	SEPSECS	Q9HD40	614
TSEN54	CLP1	Q92989	587
TSEN54	CHMP1A	Q9HD42	580
TSEN54	TRPT1	Q86TN4	529
TSEN54	AMPD2	Q01433	488
TSEN54	ARL1	P40616	469
TSEN54	EXOSC9	Q06265	459
TSEN54	ARFGAP2	Q8N6H7	447

IntAct

91 interactions, top by confidence:

A	B	Type	Score
TSEN2	TSEN54	psi-mi:“MI:0915”(physical association)	0.830
TSEN54	TSEN2	psi-mi:“MI:0915”(physical association)	0.830
TSEN2	TSEN54	psi-mi:“MI:0914”(association)	0.830
TSEN15	TSEN54	psi-mi:“MI:0914”(association)	0.740
TSEN15	TSEN54	psi-mi:“MI:0915”(physical association)	0.740
TSEN54	CLP1	psi-mi:“MI:0915”(physical association)	0.670
CLP1	PCF11	psi-mi:“MI:0914”(association)	0.590
GOLGA6L9	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	LHX4	psi-mi:“MI:0915”(physical association)	0.560
RINT1	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
KRT31	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	TRIML2	psi-mi:“MI:0915”(physical association)	0.560
KPNA5	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	NCKIPSD	psi-mi:“MI:0915”(physical association)	0.560
NAA10	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	MRPL38	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	NFKBID	psi-mi:“MI:0915”(physical association)	0.560
LMO2	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
TSEN54	LHX3	psi-mi:“MI:0915”(physical association)	0.560
IRF4	TSEN54	psi-mi:“MI:0915”(physical association)	0.560
AMMECR1	HNRNPF	psi-mi:“MI:0914”(association)	0.530

BioGRID (50): TSEN54 (Two-hybrid), TSEN54 (Affinity Capture-RNA), TSEN54 (Affinity Capture-RNA), TSEN54 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN54 (Two-hybrid), TSEN54 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN34 (Affinity Capture-MS), TSEN15 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS)

ESM2 similar proteins: A1L1C2, A2RRU4, A6QM06, A6QP75, E1BE10, E2RD63, G5E872, O75888, P29376, P70295, P97260, Q12770, Q1LZ97, Q28DT3, Q2M2I3, Q3TAA7, Q3U5Q7, Q3ZCA1, Q4FZD7, Q5EBM0, Q5MNU5, Q5SWZ9, Q60I26, Q60I27, Q69Z89, Q6AZ51, Q6GQT6, Q6IN84, Q6NUI2, Q6P9U1, Q7Z6J9, Q8BH06, Q8BTM9, Q8C0R7, Q8IYL2, Q8N1F8, Q8N2A8, Q8NAC3, Q8NFR9, Q8TDF6

Diamond homologs: O74908, Q7Z6J9, Q8C2A2, Q02825, Q74ZJ5, Q7SC91

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	19
Uncertain significance	217
Likely benign	277
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069583	NM_207346.3(TSEN54):c.524_525del (p.Ser175fs)	Pathogenic
1180778	NM_207346.3(TSEN54):c.1252+1G>T	Pathogenic
1323718	NM_207346.3(TSEN54):c.1431-2A>G	Pathogenic
1395769	NM_207346.3(TSEN54):c.103dup (p.Gln35fs)	Pathogenic
160125	NM_207346.3(TSEN54):c.1138G>T (p.Glu380Ter)	Pathogenic
160136	NM_207346.3(TSEN54):c.575_576del (p.His192fs)	Pathogenic
1686281	NM_207346.3(TSEN54):c.221+3G>T	Pathogenic
1705655	NM_207346.3(TSEN54):c.869_875dup (p.Lys293fs)	Pathogenic
180672	NM_207346.3(TSEN54):c.468+2T>C	Pathogenic
1957365	NM_207346.3(TSEN54):c.580dup (p.Glu194fs)	Pathogenic
2120	NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)	Pathogenic
2123	NM_207346.3(TSEN54):c.1027C>T (p.Gln343Ter)	Pathogenic
212451	NM_207346.3(TSEN54):c.1386_1387insTA (p.Lys463Ter)	Pathogenic
212452	NM_207346.3(TSEN54):c.1397dup (p.Gly467fs)	Pathogenic
212454	NM_207346.3(TSEN54):c.823del (p.Val275fs)	Pathogenic
2127465	NM_207346.3(TSEN54):c.203_204dup (p.Gln69fs)	Pathogenic
2445207	NM_207346.3(TSEN54):c.953del (p.Pro318fs)	Pathogenic
265282	NM_207346.3(TSEN54):c.670_671del (p.Lys224fs)	Pathogenic
2697775	NM_207346.3(TSEN54):c.1087C>T (p.Gln363Ter)	Pathogenic
2703247	NM_207346.3(TSEN54):c.486_487insGGAG (p.Arg163fs)	Pathogenic
2735393	NM_207346.3(TSEN54):c.692del (p.Pro231fs)	Pathogenic
2747640	NM_207346.3(TSEN54):c.604_605del (p.Arg202fs)	Pathogenic
2763079	NM_207346.3(TSEN54):c.696del (p.Cys234fs)	Pathogenic
2763503	NM_207346.3(TSEN54):c.1207C>T (p.Gln403Ter)	Pathogenic
2786735	NM_207346.3(TSEN54):c.1264C>T (p.Gln422Ter)	Pathogenic
2795772	NM_207346.3(TSEN54):c.449_450del (p.Val150fs)	Pathogenic
2804488	NM_207346.3(TSEN54):c.869dup (p.Ala291fs)	Pathogenic
2823132	NM_207346.3(TSEN54):c.291del (p.Lys97fs)	Pathogenic
2831248	NM_207346.3(TSEN54):c.302_317del (p.Thr101fs)	Pathogenic
2837939	NM_207346.3(TSEN54):c.670A>T (p.Lys224Ter)	Pathogenic

SpliceAI

1917 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75516745:GC:G	acceptor_gain	1.0000
17:75516867:G:GT	donor_gain	1.0000
17:75516867:G:T	donor_gain	1.0000
17:75516907:GCCT:G	donor_gain	1.0000
17:75516911:G:GG	donor_gain	1.0000
17:75516919:G:T	donor_gain	1.0000
17:75516929:GGG:G	donor_gain	1.0000
17:75516930:GGG:G	donor_gain	1.0000
17:75517070:GCG:G	donor_gain	1.0000
17:75517241:GTGT:G	donor_gain	1.0000
17:75517651:ACCAG:A	donor_loss	1.0000
17:75517653:CAG:C	donor_loss	1.0000
17:75517654:AG:A	donor_loss	1.0000
17:75517655:GGTAT:G	donor_loss	1.0000
17:75517657:T:A	donor_loss	1.0000
17:75517703:A:AG	donor_gain	1.0000
17:75518686:C:G	donor_gain	1.0000
17:75518991:T:TA	acceptor_gain	1.0000
17:75519045:AAGGT:A	donor_loss	1.0000
17:75519048:G:GA	donor_loss	1.0000
17:75519049:T:G	donor_loss	1.0000
17:75522306:C:G	donor_gain	1.0000
17:75523273:A:AG	acceptor_gain	1.0000
17:75523274:G:GA	acceptor_gain	1.0000
17:75523274:GCC:G	acceptor_gain	1.0000
17:75523274:GCCGT:G	acceptor_gain	1.0000
17:75523657:TGTCA:T	acceptor_loss	1.0000
17:75523658:GTCAG:G	acceptor_loss	1.0000
17:75523659:TCAG:T	acceptor_loss	1.0000
17:75523660:CAG:C	acceptor_loss	1.0000

AlphaMissense

3412 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75517234:T:C	L120P	0.997
17:75519008:T:C	L161P	0.996
17:75517167:T:C	F98L	0.995
17:75517169:C:A	F98L	0.995
17:75517169:C:G	F98L	0.995
17:75517059:T:C	L91S	0.994
17:75517224:G:C	A117P	0.994
17:75524339:C:A	A503D	0.994
17:75517182:G:C	G103R	0.993
17:75517210:T:C	L112P	0.992
17:75519012:G:C	K162N	0.992
17:75519012:G:T	K162N	0.992
17:75519029:T:A	V168D	0.992
17:75517031:T:A	W82R	0.991
17:75517031:T:C	W82R	0.991
17:75517170:T:A	W99R	0.991
17:75517170:T:C	W99R	0.991
17:75523764:G:C	R472P	0.991
17:75517026:C:A	A80D	0.990
17:75517605:G:C	A140P	0.990
17:75519020:G:T	G165V	0.990
17:75523730:T:C	F461L	0.990
17:75523732:C:A	F461L	0.990
17:75523732:C:G	F461L	0.990
17:75517210:T:A	L112H	0.989
17:75517237:T:C	L121P	0.989
17:75517650:T:G	Y155D	0.989
17:75518998:T:C	F158L	0.989
17:75519000:C:A	F158L	0.989
17:75519000:C:G	F158L	0.989

dbSNP variants (sampled 300 via entrez): RS1000158460 (17:75522465 A>G), RS1000212175 (17:75519934 G>A), RS1000305124 (17:75524960 G>A,C), RS1000407484 (17:75520100 C>G,T), RS1000440720 (17:75525173 A>G), RS1000794032 (17:75525161 C>T), RS1000983325 (17:75515599 G>A,C), RS1001317005 (17:75515835 C>T), RS1001810738 (17:75524656 A>G), RS1001873980 (17:75514746 GC>G,GCC), RS1002052945 (17:75519664 G>A), RS1002203148 (17:75520750 T>C), RS1002494620 (17:75515416 G>T), RS1002511511 (17:75523301 C>A,G,T), RS1002511678 (17:75519861 C>T)

Disease associations

OMIM: gene MIM:608755 | disease phenotypes: MIM:277470, MIM:610204, MIM:225753, MIM:607596, MIM:213000, MIM:277410, MIM:614482

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 5	Strong	Autosomal recessive
pontocerebellar hypoplasia type 4	Strong	Autosomal recessive
pontocerebellar hypoplasia type 2A	Strong	Autosomal recessive
pontocerebellar hypoplasia type 2	Supportive	Autosomal recessive
cerebellar ataxia	Limited	Autosomal dominant

Mondo (13): pontocerebellar hypoplasia type 2A (MONDO:0010190), pontocerebellar hypoplasia type 5 (MONDO:0012438), congenital nervous system disorder (MONDO:0002320), pontocerebellar hypoplasia type 4 (MONDO:0009166), pontocerebellar hypoplasia (MONDO:0020135), amblyopia (MONDO:0001020), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), methylmalonic aciduria and homocystinuria type cblD (MONDO:0010185), Huppke-Brendel syndrome (MONDO:0013772), pontocerebellar hypoplasia type 2 (MONDO:0016759), cerebellar ataxia (MONDO:0000437)

Orphanet (10): Pontocerebellar hypoplasia type 2 (Orphanet:2524), Pontocerebellar hypoplasia type 5 (Orphanet:166068), Pontocerebellar hypoplasia type 4 (Orphanet:166063), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Congenital cataract-hearing loss-severe developmental delay syndrome (Orphanet:300313), Homocystinuria without methylmalonic aciduria (Orphanet:622), Methylmalonic acidemia with homocystinuria, type cblD (Orphanet:79283), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000505	Visual impairment
HP:0000648	Optic atrophy
HP:0000711	Restlessness
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001522	Death in infancy
HP:0001561	Polyhydramnios
HP:0001999	Abnormal facial shape
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002123	Generalized myoclonic seizure
HP:0002171	Gliosis

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003042_1	Sight-threatening diabetic retinopathy in type 2 diabetes	7.000000e-07
GCST004183_32	Lung function (FEV1)	2.000000e-06
GCST007429_76	Lung function (FVC)	1.000000e-07
GCST007431_132	Lung function (FEV1/FVC)	7.000000e-06
GCST007432_193	FEV1	2.000000e-13
GCST008660_7	Lung function in never smokers (high FEV1 vs average FEV1)	5.000000e-07
GCST008662_1	Lung function in never smokers (low FEV1 vs high FEV1)	1.000000e-08
GCST010727_38	Deep white matter hyperintensities	3.000000e-07
GCST90002400_231	Plateletcrit	1.000000e-09
GCST90002402_416	Platelet count	2.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004312	vital capacity
EFO:0004713	FEV/FVC ratio
EFO:0005665	white matter hyperintensity measurement
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D000550	Amblyopia	C10.228.140.055; C10.597.751.941.073; C11.966.073; C23.888.592.763.941.073
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C562568	Cerebellar Hypoplasia (supp.)
C564743	Methylmalonic Aciduria and Homocystinuria, CblD Type (supp.)
C537745	Olivopontocerebellar hypoplasia, fetal-onset (supp.)
C580383	Pontocerebellar Hypoplasia (supp.)
C548070	Pontocerebellar Hypoplasia Type 2 (supp.)
C564738	Pontocerebellar Hypoplasia Type 2A (supp.)
C536716	Young McKeever Squier syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	3
aristolochic acid I	increases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Doxorubicin	increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Polychlorinated Biphenyls	affects expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Thiram	decreases expression	1
Cadmium Chloride	decreases expression	1
1-Butanol	affects cotreatment, increases abundance, increases expression	1
Particulate Matter	increases expression, affects cotreatment, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00094614	PHASE4	COMPLETED	Trial Comparing Daily Atropine Versus Weekend Atropine
NCT03109314	PHASE4	COMPLETED	Combining Donepezil With Perceptual Learning in Normal and Amblyopic Human The Effect of Donepezil on Perceptual Learning in Adult Amblyopia
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00000170	PHASE3	COMPLETED	Occlusion Versus Pharmacologic Therapy for Moderate Amblyopia
NCT00001864	PHASE3	COMPLETED	Amblyopia (Lazy Eye) Treatment Study
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
NCT00091923	PHASE3	COMPLETED	Trial to Evaluate 2 Hours of Daily Patching for Amblyopia in Children
NCT00094679	PHASE3	COMPLETED	Trial Comparing Part-time Versus Minimal-time Patching for Moderate Amblyopia
NCT00094692	PHASE3	COMPLETED	An Evaluation of Treatment of Amblyopia in Children 7 To <18 Years Old
NCT00094744	PHASE3	COMPLETED	Trial Comparing Part-time Versus Full-time Patching for Severe Amblyopia
NCT00131729	PHASE3	COMPLETED	Electronic Recording of Compliance With Occlusion Therapy for Amblyopia
NCT00315198	PHASE3	COMPLETED	Trial Comparing Near Versus Distance Activities While Patching for Amblyopia in Children 3 to <7 Years Old
NCT00315302	PHASE3	COMPLETED	Trial Comparing Atropine to Atropine Plus a Plano Lens for the Sound Eye for Amblyopia in Children 3 to <7 Years Old
NCT00315328	PHASE3	COMPLETED	Trial Comparing Patching Versus Atropine for Amblyopia in 7 to < 13 Year Olds
NCT00506675	PHASE3	TERMINATED	Combined Patching-Atropine for Residual Amblyopia
NCT00525174	PHASE3	COMPLETED	Full-time Bangerter Filters Versus Part-time Daily Patching for Moderate Amblyopia in Children
NCT00587171	PHASE3	TERMINATED	Trial Comparing Patching With Active Vision Therapy to Patching With Control Vision Therapy as Treatment for Amblyopia
NCT00944710	PHASE3	COMPLETED	Augmenting Atropine Treatment for Amblyopia in Children 3 to < 8 Years Old
NCT00945100	PHASE3	COMPLETED	Increasing Patching for Amblyopia in Children 3 to < 8 Years Old
NCT01190813	PHASE3	COMPLETED	Levodopa for the Treatment of Residual Amblyopia
NCT04378790	PHASE3	RECRUITING	A Randomized Trial to Evaluate Sequential vs Simultaneous Patching
NCT06380517	PHASE3	RECRUITING	Dichoptic Treatment for Amblyopia in Children 4 to 7 Years of Age
NCT06524882	PHASE3	RECRUITING	Dichoptic Treatment for Amblyopia in Children 8 to 12 Years of Age
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia