TSEN2

Summary

TSEN2 (tRNA splicing endonuclease subunit 2, HGNC:28422) is a protein-coding gene on chromosome 3p25.2, encoding tRNA-splicing endonuclease subunit Sen2 (Q8NCE0). Constitutes one of the two 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 selective cancer dependency (DepMap: 76.2% of cell lines).

This gene encodes one of the subunits of the tRNA splicing endonuclease. This endonuclease catalyzes the first step in RNA splicing which is the removal of introns. Mutations in this gene have been associated with pontocerebellar hypoplasia type 2. A pseudogene has been identified on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 80746 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 2B (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 26
• Clinical variants (ClinVar): 345 total — 8 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 61
• Cancer dependency (DepMap): dependent in 76.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_025265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28422
Approved symbol	TSEN2
Name	tRNA splicing endonuclease subunit 2
Location	3p25.2
Locus type	gene with protein product
Status	Approved
Aliases	SEN2, SEN2L, MGC2776
Ensembl gene	ENSG00000154743
Ensembl biotype	protein_coding
OMIM	608753
Entrez	80746

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 34 protein_coding, 28 nonsense_mediated_decay, 7 retained_intron

ENST00000284995, ENST00000402228, ENST00000412698, ENST00000415684, ENST00000444864, ENST00000446004, ENST00000454502, ENST00000455118, ENST00000473755, ENST00000475595, ENST00000490981, ENST00000679367, ENST00000679420, ENST00000679424, ENST00000679425, ENST00000679492, ENST00000679537, ENST00000679555, ENST00000679670, ENST00000679690, ENST00000679693, ENST00000679699, ENST00000679756, ENST00000679785, ENST00000679835, ENST00000679876, ENST00000679995, ENST00000680126, ENST00000680172, ENST00000680264, ENST00000680275, ENST00000680354, ENST00000680376, ENST00000680419, ENST00000680421, ENST00000680449, ENST00000680458, ENST00000680555, ENST00000680598, ENST00000680765, ENST00000680817, ENST00000680857, ENST00000680873, ENST00000680923, ENST00000680943, ENST00000680986, ENST00000681042, ENST00000681073, ENST00000681140, ENST00000681227, ENST00000681268, ENST00000681343, ENST00000681433, ENST00000681471, ENST00000681482, ENST00000681676, ENST00000681713, ENST00000877377, ENST00000877378, ENST00000877379, ENST00000877380, ENST00000877381, ENST00000877382, ENST00000877383, ENST00000929195, ENST00000929196, ENST00000929197, ENST00000958146, ENST00000958147

RefSeq mRNA: 7 — MANE Select: NM_025265 NM_001145392, NM_001145393, NM_001145394, NM_001321277, NM_001321278, NM_001321279, NM_025265

CCDS: CCDS2611, CCDS46757, CCDS46758, CCDS93216

Canonical transcript exons

ENST00000284995 — 12 exons

Exon	Start	End
ENSE00001017419	12529762	12529873
ENSE00001077532	12505154	12505231
ENSE00003506094	12531570	12531659
ENSE00003510862	12503262	12503784
ENSE00003547473	12516611	12516661
ENSE00003556253	12519059	12519197
ENSE00003561225	12492136	12492217
ENSE00003574621	12496518	12496554
ENSE00003691728	12489784	12489989
ENSE00003789297	12528888	12528924
ENSE00003892827	12484480	12484880
ENSE00003896223	12532662	12533658

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 90.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.3230 / max 78.0778, expressed in 1501 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35381	3.8652	1455
202680	0.4577	277

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	90.77	gold quality
mucosa of transverse colon	UBERON:0004991	89.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.16	gold quality
ventricular zone	UBERON:0003053	86.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.02	gold quality
gastrocnemius	UBERON:0001388	85.97	gold quality
body of pancreas	UBERON:0001150	85.95	gold quality
cerebellar hemisphere	UBERON:0002245	85.83	gold quality
cerebellar cortex	UBERON:0002129	85.72	gold quality
right uterine tube	UBERON:0001302	85.53	gold quality
muscle of leg	UBERON:0001383	85.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.41	gold quality
right ovary	UBERON:0002118	85.37	gold quality
tibial nerve	UBERON:0001323	85.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.35	gold quality
left ovary	UBERON:0002119	85.34	gold quality
transverse colon	UBERON:0001157	85.31	gold quality
cortical plate	UBERON:0005343	84.94	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.47	gold quality
left uterine tube	UBERON:0001303	84.36	gold quality
cerebellum	UBERON:0002037	84.29	gold quality
body of uterus	UBERON:0009853	84.15	gold quality
metanephros cortex	UBERON:0010533	83.84	gold quality
right atrium auricular region	UBERON:0006631	83.75	gold quality
body of stomach	UBERON:0001161	83.61	gold quality
ectocervix	UBERON:0012249	83.58	gold quality
adenohypophysis	UBERON:0002196	83.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.46	gold quality
ganglionic eminence	UBERON:0004023	83.36	gold quality
sural nerve	UBERON:0015488	83.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting TSEN2, 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-4776-3P	100.00	68.73	1340
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-4687-5P	99.14	66.26	488
HSA-MIR-6780B-3P	99.13	67.18	622
HSA-MIR-143-5P	98.98	68.87	946
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-6511A-3P	97.60	66.61	713
HSA-MIR-6511B-3P	97.60	66.61	713
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-4315	94.78	64.86	112

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 76.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome. (PMID:34964109)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsen2	ENSDARG00000091851
mus_musculus	Tsen2	ENSMUSG00000042389
rattus_norvegicus	Tsen2	ENSRNOG00000060175
drosophila_melanogaster	Tsen2	FBGN0051812
caenorhabditis_elegans		WBGENE00013231

Protein

Protein identifiers

tRNA-splicing endonuclease subunit Sen2 — Q8NCE0 (reviewed: Q8NCE0)

Alternative names: tRNA-intron endonuclease Sen2

All UniProt accessions (20): Q8NCE0, A0A7P0T841, A0A7P0T8F8, A0A7P0T8I7, A0A7P0T8K4, A0A7P0T8S9, A0A7P0T8W9, A0A7P0T8Z6, A0A7P0T914, A0A7P0T923, A0A7P0T974, A0A7P0T9K6, A0A7P0T9Y6, A0A7P0TA86, A0A7P0TBE6, A0A7P0Z492, A0A7P0Z4J6, C9J7Z4, H7C2Z3, H7C301

UniProt curated annotations — full annotation on UniProt →

Function. Constitutes one of the two 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. Isoform 1 probably carries the active site for 5’-splice site cleavage. 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. Isoform 2 is responsible for processing a yet unknown RNA substrate. The complex containing isoform 2 is not able to cleave pre-tRNAs properly, although it retains endonucleolytic activity.

Subunit / interactions. tRNA splicing endonuclease is a heterotetramer composed of isoform 1 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. Isoform 2 belongs to a different complex that contains TSEN54 but low level of TSEN15 and TSEN34/LENG5.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Isoform 1 and isoform 2 are widely expressed at very low level.

Disease relevance. Pontocerebellar hypoplasia 2B (PCH2B) [MIM:612389] 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.

Similarity. Belongs to the tRNA-intron endonuclease family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8NCE0-1	1	yes
Q8NCE0-2	2, SEN2deltaEx8, DeltaEx8
Q8NCE0-3	3
Q8NCE0-4	4
Q8NCE0-5	5

RefSeq proteins (7): NP_001138864, NP_001138865, NP_001138866, NP_001308206, NP_001308207, NP_001308208, NP_079541* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006676	tRNA_splic	Family
IPR006677	tRNA_intron_Endonuc_cat-like	Domain
IPR006678	tRNA_intron_Endonuc_N	Domain
IPR011856	tRNA_endonuc-like_dom_sf	Homologous_superfamily
IPR016589	tRNA_splic_SEN2	Family
IPR036167	tRNA_intron_Endo_cat-like_sf	Homologous_superfamily

Pfam: PF01974, PF02778

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 (48 total): strand 15, helix 10, splice variant 5, turn 5, sequence variant 3, active site 3, modified residue 3, sequence conflict 2, chain 1, region of interest 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-Q8NCE0-F1	73.63	0.55

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 (3): 369; 377; 416

Post-translational modifications (3): 408, 411, 415

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: 248 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, TGCGCANK_UNKNOWN, GOMF_NUCLEASE_ACTIVITY, GOBP_TRNA_METABOLIC_PROCESS, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION, GOBP_RNA_SPLICING, MARIADASON_REGULATED_BY_HISTONE_ACETYLATION_DN, AP2_Q6_01, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOCC_NUCLEOLUS, MANALO_HYPOXIA_DN

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 (4): tRNA-intron lyase activity (GO:0000213), nucleic acid binding (GO:0003676), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (7): tRNA-intron endonuclease complex (GO:0000214), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), 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
cellular anatomical structure	3
binding	2
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
RNA endonuclease activity	1
tRNA-specific ribonuclease activity	1
phosphorus-oxygen lyase activity	1
catalytic activity	1
nuclear protein-containing complex	1
endoribonuclease complex	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSEN2	TSEN54	Q7Z6J9	999
TSEN2	TSEN15	Q8WW01	999
TSEN2	TSEN34	Q9BSV6	999
TSEN2	CPSF6	Q16630	804
TSEN2	CLP1	Q92989	774
TSEN2	RARS2	Q5T160	744
TSEN2	SETX	Q7Z333	680
TSEN2	SEPSECS	Q9HD40	680
TSEN2	ST7	Q9NRC1	580
TSEN2	TRPT1	Q86TN4	559
TSEN2	EXOSC3	Q9NQT5	556
TSEN2	PCF11	O94913	547
TSEN2	VRK1	Q99986	532
TSEN2	RTCB	Q9Y3I0	489
TSEN2	TOE1	Q96GM8	469

IntAct

60 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
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
TSEN2	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
TAX1BP1	TSEN2	psi-mi:“MI:0915”(physical association)	0.560
CADPS	TSEN2	psi-mi:“MI:0915”(physical association)	0.560
CTAG2	TSEN2	psi-mi:“MI:0915”(physical association)	0.560
TSEN2	GABPB2	psi-mi:“MI:0915”(physical association)	0.560
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
Clp1	TSEN34	psi-mi:“MI:0915”(physical association)	0.400
TSEN15	TSEN54	psi-mi:“MI:0914”(association)	0.350
SSB	RPS3A	psi-mi:“MI:0914”(association)	0.350
GRIN2C	MANBA	psi-mi:“MI:0914”(association)	0.350
CIB2	PLD2	psi-mi:“MI:0914”(association)	0.350
ZXDB	SETD1A	psi-mi:“MI:0914”(association)	0.350
THUMPD3	TRMU	psi-mi:“MI:0914”(association)	0.350
ICAM4	ATE1	psi-mi:“MI:0914”(association)	0.350
RTBDN	COL6A1	psi-mi:“MI:0914”(association)	0.350
TSEN2	TMED8	psi-mi:“MI:0914”(association)	0.350
TIMM50	ZNF320	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): TSEN54 (Two-hybrid), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), GREB1L (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TMED8 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), CLP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2TTB3, A0JMR6, A4IIA7, F4JNY0, F6RRD7, I3XHK1, O60934, O88622, P14629, P28715, P79457, Q08DZ8, Q12789, Q17RS7, Q1LWH4, Q28I29, Q32PL8, Q3B7T1, Q4R7Q1, Q5FWP4, Q5M954, Q5QJC2, Q5RA37, Q5RCV3, Q5ZIN2, Q66J91, Q6GQV7, Q6NVF4, Q6P1E7, Q6P1H6, Q6P256, Q6P7W5, Q76CY8, Q7TP65, Q86W56, Q8BMI4, Q8C0W1, Q8C5W4, Q8GT06, Q8IXW5

Diamond homologs: A1RSY7, A2BIW2, A4WLV3, A6UPD9, B0R7C0, B1Y9D1, B6YXU4, C3MQX7, C3MWW5, C3N6N2, C3N746, C3NGJ0, C4KIA4, C5A2D9, O07118, O07165, O29362, O58033, P16658, Q12X51, Q3IU70, Q46FK9, Q4JAF4, Q58819, Q5JHP5, Q5M954, Q5UYF6, Q5Z6B1, Q5ZIN2, Q6L1P9, Q6LY59, Q6P7W5, Q74MP4, Q74ZY5, Q7SAK9, Q8BMZ5, Q8NCE0, Q8PZI1, Q8TGX1, Q8TGZ5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	15
Uncertain significance	147
Likely benign	91
Benign	50

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1031439	NM_025265.4(TSEN2):c.770_776delinsCA (p.Tyr257fs)	Pathogenic
180670	NM_025265.4(TSEN2):c.934G>A (p.Gly312Arg)	Pathogenic
180671	NM_025265.4(TSEN2):c.691C>T (p.Gln231Ter)	Pathogenic
2228672	NM_025265.4(TSEN2):c.215C>A (p.Ser72Ter)	Pathogenic
3658805	NM_025265.4(TSEN2):c.917del (p.Phe306fs)	Pathogenic
3692161	NM_025265.4(TSEN2):c.1016del (p.Phe339fs)	Pathogenic
4803181	NM_025265.4(TSEN2):c.583G>T (p.Glu195Ter)	Pathogenic
4811769	NM_025265.4(TSEN2):c.790del (p.Glu264fs)	Pathogenic
1334772	NM_025265.4(TSEN2):c.904G>A (p.Glu302Lys)	Likely pathogenic
1428757	NM_025265.4(TSEN2):c.1099+1G>A	Likely pathogenic
180669	NM_025265.4(TSEN2):c.960+1_960+5del	Likely pathogenic
2067508	NM_025265.4(TSEN2):c.1100-2A>C	Likely pathogenic
212442	NM_025265.4(TSEN2):c.1337A>G (p.Gln446Arg)	Likely pathogenic
212443	NM_025265.4(TSEN2):c.138CAA[1] (p.Asn48del)	Likely pathogenic
2683805	NM_025265.4(TSEN2):c.1100-5T>A	Likely pathogenic
3588355	NM_025265.4(TSEN2):c.200del (p.Gly67fs)	Likely pathogenic
3588357	NM_025265.4(TSEN2):c.580C>T (p.Gln194Ter)	Likely pathogenic
3588358	NM_025265.4(TSEN2):c.695_699del (p.Arg232fs)	Likely pathogenic
4811660	NM_025265.4(TSEN2):c.190-2A>G	Likely pathogenic
4814061	NM_025265.4(TSEN2):c.1260_1264del (p.Cys421fs)	Likely pathogenic
495252	NM_025265.4(TSEN2):c.1037A>G (p.Tyr346Cys)	Likely pathogenic
495253	NM_025265.4(TSEN2):c.353_354del (p.Gln118fs)	Likely pathogenic
632396	NM_025265.4(TSEN2):c.1048C>T (p.Arg350Ter)	Likely pathogenic

SpliceAI

2581 predictions. Top by Δscore:

Variant	Effect	Δscore
3:12489765:T:TA	acceptor_gain	1.0000
3:12489780:A:AG	acceptor_gain	1.0000
3:12489782:A:AG	acceptor_gain	1.0000
3:12489783:G:GG	acceptor_gain	1.0000
3:12489985:GGAAA:G	donor_gain	1.0000
3:12489986:GAAA:G	donor_gain	1.0000
3:12489986:GAAAG:G	donor_gain	1.0000
3:12489987:A:T	donor_gain	1.0000
3:12489989:AGTA:A	donor_loss	1.0000
3:12489990:G:GG	donor_gain	1.0000
3:12489992:A:AG	donor_loss	1.0000
3:12492130:T:A	acceptor_gain	1.0000
3:12496552:GAG:G	donor_gain	1.0000
3:12496553:AGGTA:A	donor_loss	1.0000
3:12496555:GTA:G	donor_loss	1.0000
3:12496556:T:A	donor_loss	1.0000
3:12503781:GGAA:G	donor_gain	1.0000
3:12503782:GAA:G	donor_gain	1.0000
3:12503782:GAAG:G	donor_gain	1.0000
3:12503783:AA:A	donor_gain	1.0000
3:12503785:G:GG	donor_gain	1.0000
3:12505152:A:AG	acceptor_gain	1.0000
3:12505153:G:GG	acceptor_gain	1.0000
3:12519048:A:G	acceptor_gain	1.0000
3:12519051:A:AG	acceptor_gain	1.0000
3:12519198:G:GG	donor_gain	1.0000
3:12529760:A:AG	acceptor_gain	1.0000
3:12529761:G:GG	acceptor_gain	1.0000
3:12529761:GTT:G	acceptor_gain	1.0000
3:12489761:T:A	acceptor_gain	0.9900

AlphaMissense

3066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:12519158:T:A	W354R	0.998
3:12519158:T:C	W354R	0.998
3:12529770:T:A	V382D	0.998
3:12529873:G:C	K416N	0.998
3:12529873:G:T	K416N	0.998
3:12519165:C:A	P356H	0.997
3:12532680:T:A	W453R	0.997
3:12532680:T:C	W453R	0.997
3:12528917:C:G	H377D	0.996
3:12505218:T:C	L299P	0.995
3:12519083:T:A	W329R	0.995
3:12519083:T:C	W329R	0.995
3:12519147:G:C	R350P	0.995
3:12528888:T:C	L367P	0.995
3:12528902:G:C	G372R	0.995
3:12528919:T:A	H377Q	0.995
3:12528919:T:G	H377Q	0.995
3:12528921:C:A	A378E	0.995
3:12529826:T:A	W401R	0.995
3:12529826:T:C	W401R	0.995
3:12492146:G:A	G67E	0.994
3:12516611:G:C	A304P	0.994
3:12528891:T:A	L368Q	0.994
3:12528891:T:C	L368P	0.994
3:12528911:T:C	F375L	0.994
3:12528913:T:A	F375L	0.994
3:12528913:T:G	F375L	0.994
3:12532682:G:C	W453C	0.994
3:12532682:G:T	W453C	0.994
3:12519160:G:C	W354C	0.993

dbSNP variants (sampled 300 via entrez): RS1000044316 (3:12512693 A>C,G), RS1000120375 (3:12485072 C>G), RS1000180209 (3:12478467 G>A), RS1000229413 (3:12511208 G>A), RS1000241403 (3:12492099 A>T), RS1000243755 (3:12528500 A>G), RS1000245138 (3:12480780 C>A), RS1000296240 (3:12528733 C>T), RS1000334226 (3:12486247 C>A), RS1000375839 (3:12528587 G>A), RS1000390317 (3:12522847 G>A,T), RS1000403913 (3:12512360 A>C,G,T), RS1000423569 (3:12484767 G>C,T), RS1000447170 (3:12486526 T>C), RS1000518649 (3:12533197 G>A)

Disease associations

OMIM: gene MIM:608753 | disease phenotypes: MIM:612389, MIM:607596, MIM:616266

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 2B	Strong	Autosomal recessive
pontocerebellar hypoplasia type 2	Supportive	Autosomal recessive

Mondo (5): pontocerebellar hypoplasia type 2B (MONDO:0012890), pontocerebellar hypoplasia (MONDO:0020135), hemolytic-uremic syndrome (MONDO:0001549), congenital contractures of the limbs and face, hypotonia, and developmental delay (MONDO:0014556), pontocerebellar hypoplasia type 2 (MONDO:0016759)

Orphanet (4): Pontocerebellar hypoplasia type 2 (Orphanet:2524), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523), Hemolytic uremic syndrome (Orphanet:544458), Congenital limbs-face contractures-hypotonia-developmental delay syndrome (Orphanet:562528)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000340	Sloping forehead
HP:0000505	Visual impairment
HP:0000954	Single transverse palmar crease
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
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:0002059	Cerebral atrophy
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002119	Ventriculomegaly
HP:0002123	Generalized myoclonic seizure
HP:0002169	Clonus
HP:0002179	Opisthotonus
HP:0002268	Paroxysmal dystonia

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST005752_138	Systemic lupus erythematosus	9.000000e-06
GCST005956_72	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_11	Waist-to-hip ratio adjusted for BMI (age <50)	9.000000e-06
GCST005958_19	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-06
GCST005962_29	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	9.000000e-09
GCST90020024_1133	A body shape index	2.000000e-11
GCST90020025_1911	Waist-to-hip ratio adjusted for BMI	6.000000e-24
GCST90020025_1915	Waist-to-hip ratio adjusted for BMI	4.000000e-11
GCST90020025_1920	Waist-to-hip ratio adjusted for BMI	2.000000e-13
GCST90020025_1924	Waist-to-hip ratio adjusted for BMI	2.000000e-10
GCST90020025_1925	Waist-to-hip ratio adjusted for BMI	2.000000e-14
GCST90020025_1927	Waist-to-hip ratio adjusted for BMI	4.000000e-08
GCST90020026_176	Hip index	1.000000e-15
GCST90020026_182	Hip index	5.000000e-14
GCST90020026_186	Hip index	2.000000e-12
GCST90020027_154	Waist-hip index	2.000000e-11
GCST90020027_155	Waist-hip index	3.000000e-15
GCST90020027_157	Waist-hip index	5.000000e-08
GCST90020027_216	Waist-hip index	1.000000e-24
GCST90020027_220	Waist-hip index	1.000000e-11
GCST90020027_225	Waist-hip index	1.000000e-13
GCST90020028_700	Hip circumference adjusted for BMI	4.000000e-11
GCST90020028_704	Hip circumference adjusted for BMI	9.000000e-09
GCST90020028_705	Hip circumference adjusted for BMI	1.000000e-08
GCST90020029_1002	Waist circumference adjusted for body mass index	4.000000e-13
GCST90020029_1005	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006463	Hemolytic-Uremic Syndrome	C12.050.351.968.419.936.463; C12.200.777.419.936.463; C12.950.419.936.463; C15.378.050.141.610; C15.378.140.855.925.500; C15.378.243.937.925.500
C580383	Pontocerebellar Hypoplasia (supp.)
C548070	Pontocerebellar Hypoplasia Type 2 (supp.)
C567325	Pontocerebellar Hypoplasia Type 2B (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation	2
Estradiol	increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
avobenzone	decreases expression	1
pentabromodiphenyl ether	decreases expression	1
monomethylarsonous acid	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Irinotecan	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Caffeine	decreases phosphorylation	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Floxacillin	affects binding	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03776851	PHASE4	COMPLETED	Erythropoietin in Hemolytic Uremic Syndrome
NCT00004465	PHASE3	TERMINATED	Phase III Randomized Study of SYNSORB Pk in Children With E. Coli-Associated Hemolytic Uremic Syndrome
NCT01433003	PHASE3	WITHDRAWN	The Plasma Large-Volume Exchange RCT
NCT06389474	PHASE3	RECRUITING	Efficacy of INM004 in Children With STEC-HUS
NCT00531089	PHASE2	UNKNOWN	Rituximab in Patients With Relapsed or Refractory TTP-HUS
NCT05569746	PHASE2	COMPLETED	A Study to Assess Safety, Efficacy, and Pharmacokinetics of INM004 in Pediatric Patients With STEC-HUS
NCT03275792	PHASE1	WITHDRAWN	Shiga Toxin Producing Escherichia Coli (STEC) Volume Expansion
NCT04132375	PHASE2/PHASE3	TERMINATED	Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS
NCT00358306	Not specified	COMPLETED	The Role of Endothelium Dysfunction in Progression of CKD (Chronic Kidney Disease) After AKI (Acute Kidney Injury)
NCT00593229	Not specified	TERMINATED	International Registry and Biorepository for TMA(Thrombotic Microangiopathy)
NCT01406288	Not specified	COMPLETED	Outbreak of Hemolytic Uremic Syndrome Linked to Escherichia Coli of Serotype O104:H4
NCT01561248	Not specified	COMPLETED	Study of Repetitive Intestinal Lavage in Patients With EHEC Associated Hemorrhagic Colitis
NCT01666548	Not specified	COMPLETED	Haemolytic Uraemic Syndrome in Childhood: Clinical, Cognitive and Psychological Aspects
NCT02904863	Not specified	COMPLETED	Study of ‘Vascular Competence’ Profile and Endothelial Activation in the Hemolytic Uremic Syndrome in Children and Adults
NCT03580941	Not specified	UNKNOWN	Usefulness of a Diagnostic Algorithm to Diagnose Thrombotic Microangiopathies in Pregnancy
NCT04745195	Not specified	RECRUITING	Complement Prospective Evaluation of Thrombotic Microangiopathy on Endothelium
NCT05219110	Not specified	RECRUITING	Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection
NCT05985122	Not specified	ACTIVE_NOT_RECRUITING	New Analytic Tools for aHUS and C3G Diagnosis
NCT05991245	Not specified	UNKNOWN	French National Cohort MATRIX Renal and Systemic Thrombotic Microangiopathy