SKIC3

Summary

SKIC3 (SKI3 subunit of superkiller complex, HGNC:23639) is a protein-coding gene on chromosome 5q15, encoding Superkiller complex protein 3 (Q6PGP7). Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.

This gene encodes a protein with twenty tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Mutations in this gene are associated with trichohepatoenteric syndrome.

Source: NCBI Gene 9652 — RefSeq curated summary.

At a glance

• Gene–disease (curated): trichohepatoenteric syndrome 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,622 total — 119 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_014639

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23639
Approved symbol	SKIC3
Name	SKI3 subunit of superkiller complex
Location	5q15
Locus type	gene with protein product
Status	Approved
Aliases	THES, SKI3
Ensembl gene	ENSG00000198677
Ensembl biotype	protein_coding
OMIM	614589
Entrez	9652

Gene structure

Transcript identifiers

Ensembl transcripts: 72 — 29 retained_intron, 20 nonsense_mediated_decay, 18 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000358746, ENST00000502768, ENST00000503279, ENST00000504421, ENST00000505578, ENST00000506007, ENST00000507805, ENST00000510228, ENST00000513232, ENST00000513823, ENST00000514952, ENST00000515176, ENST00000515207, ENST00000649566, ENST00000698450, ENST00000698451, ENST00000698452, ENST00000698453, ENST00000698454, ENST00000698455, ENST00000698456, ENST00000698457, ENST00000698458, ENST00000698459, ENST00000698460, ENST00000698461, ENST00000698462, ENST00000698463, ENST00000698464, ENST00000698465, ENST00000698466, ENST00000698467, ENST00000698468, ENST00000698469, ENST00000698470, ENST00000698471, ENST00000698472, ENST00000698473, ENST00000698474, ENST00000698475, ENST00000698476, ENST00000698477, ENST00000698478, ENST00000698479, ENST00000698480, ENST00000698481, ENST00000698482, ENST00000698483, ENST00000698484, ENST00000698485, ENST00000698486, ENST00000698487, ENST00000698488, ENST00000698489, ENST00000698490, ENST00000698491, ENST00000698492, ENST00000698493, ENST00000698494, ENST00000698495, ENST00000698496, ENST00000698497, ENST00000698498, ENST00000901192, ENST00000901193, ENST00000918735, ENST00000918736, ENST00000918737, ENST00000969287, ENST00000969288, ENST00000969289, ENST00000969290

RefSeq mRNA: 1 — MANE Select: NM_014639 NM_014639

CCDS: CCDS4072

Canonical transcript exons

ENST00000358746 — 43 exons

Exon	Start	End
ENSE00001083111	95543184	95543327
ENSE00001206887	95516672	95516750
ENSE00001394296	95547061	95547151
ENSE00003558178	95540690	95540830
ENSE00003578097	95537043	95537141
ENSE00003580113	95536817	95536925
ENSE00003624715	95541305	95541380
ENSE00003693040	95541815	95541906
ENSE00003973686	95550581	95550650
ENSE00003973687	95529001	95529102
ENSE00003973688	95469780	95469910
ENSE00003973689	95502880	95503003
ENSE00003973690	95530089	95530229
ENSE00003973695	95463894	95464681
ENSE00003973700	95503814	95503938
ENSE00003973701	95497416	95497488
ENSE00003973702	95498370	95498591
ENSE00003973703	95509594	95509687
ENSE00003973706	95517146	95517322
ENSE00003973714	95525398	95525501
ENSE00003973716	95490908	95491036
ENSE00003973732	95513571	95513645
ENSE00003973740	95482473	95482631
ENSE00003973747	95467866	95467989
ENSE00003973750	95512477	95512618
ENSE00003973751	95525587	95525673
ENSE00003973754	95484724	95484845
ENSE00003973756	95548560	95548715
ENSE00003973760	95516916	95517060
ENSE00003973762	95554936	95554977
ENSE00003973763	95523202	95523326
ENSE00003973764	95494964	95495017
ENSE00003973769	95478290	95478442
ENSE00003973770	95516353	95516409
ENSE00003973773	95516525	95516586
ENSE00003973774	95514855	95514923
ENSE00003973776	95528013	95528152
ENSE00003973778	95522054	95522307
ENSE00003973779	95523655	95523834
ENSE00003973780	95494682	95494793
ENSE00003973782	95506934	95507011
ENSE00003973785	95520716	95520818
ENSE00003973788	95524465	95524591

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1347 / max 976.0458, expressed in 1771 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62646	35.1347	1771

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.49	gold quality
adrenal tissue	UBERON:0018303	96.82	gold quality
stromal cell of endometrium	CL:0002255	95.88	gold quality
upper leg skin	UBERON:0004262	95.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.71	gold quality
skin of hip	UBERON:0001554	95.69	gold quality
cerebellar hemisphere	UBERON:0002245	95.29	gold quality
cerebellar cortex	UBERON:0002129	95.18	gold quality
germinal epithelium of ovary	UBERON:0001304	95.14	gold quality
colonic epithelium	UBERON:0000397	95.04	gold quality
biceps brachii	UBERON:0001507	94.63	gold quality
body of pancreas	UBERON:0001150	94.59	gold quality
skin of abdomen	UBERON:0001416	94.54	gold quality
sural nerve	UBERON:0015488	94.54	gold quality
skin of leg	UBERON:0001511	94.29	gold quality
jejunal mucosa	UBERON:0000399	94.17	gold quality
zone of skin	UBERON:0000014	94.13	gold quality
cerebellum	UBERON:0002037	93.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.81	gold quality
tibia	UBERON:0000979	93.78	gold quality
rectum	UBERON:0001052	93.76	gold quality
blood vessel layer	UBERON:0004797	93.74	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.69	gold quality
gluteal muscle	UBERON:0002000	93.67	gold quality
right ovary	UBERON:0002118	93.42	gold quality
ganglionic eminence	UBERON:0004023	93.41	gold quality
jejunum	UBERON:0002115	93.40	gold quality
left ovary	UBERON:0002119	93.39	gold quality
superficial temporal artery	UBERON:0001614	93.32	gold quality
mucosa of stomach	UBERON:0001199	93.16	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	496.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting SKIC3, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-335-3P	99.93	73.36	4958
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-205-3P	99.92	69.92	3165
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-5004-3P	99.54	68.27	1371

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). (PMID:20176027)
• TTC37 is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung, and intestine. In contrast, TTC37 is not expressed in the liver, an organ that is not consistently affected in tricho-hepato-enteric syndrome (PMID:21120949)
• This is a report of novel mutations in TTC37 in individuals of East Asian descent. * Whole exome sequencing (WES) can be useful in certain complex cases with diagnostic dilemmas. (PMID:25976726)
• A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases (PMID:26945392)
• Study reported three point mutations, which have not been previously described in other patients with THES in SKIV2L and TTC37 genes, including one nonsense, one frameshift, and one missense mutations. (PMID:27050310)
• we present seven patients from two families with a new mutation in TTC37. The phenotype is classic, but the disease course is milder, with better intra- and extrauterine growth, less need for parenteral nutrition, and better chance of survival. (PMID:29383842)
• We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment. (PMID:29527791)
• Expanding the clinical spectrum in trichohepatoenteric syndrome. (PMID:34037310)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	skic3	ENSDARG00000074314
mus_musculus	Skic3	ENSMUSG00000033991
rattus_norvegicus	Skic3	ENSRNOG00000040297
drosophila_melanogaster	CG8777	FBGN0033376

Protein

Protein identifiers

Superkiller complex protein 3 — Q6PGP7 (reviewed: Q6PGP7)

Alternative names: Tetratricopeptide repeat protein 37, Tricho-hepatic-enteric syndrome protein

All UniProt accessions (22): Q6PGP7, A0A8V8TLR0, A0A8V8TLS3, A0A8V8TLT2, A0A8V8TLT7, A0A8V8TLU2, A0A8V8TLU5, A0A8V8TM98, A0A8V8TMA3, A0A8V8TMA8, A0A8V8TMB2, A0A8V8TN82, A0A8V8TN92, A0A8V8TNA2, A0A8V8TNJ4, A0A8V8TNJ9, A0A8V8TNK4, A0A8V8TNK9, D6RCE2, D6RDA0, H0Y915, H0Y964

UniProt curated annotations — full annotation on UniProt →

Function. Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways. The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3’-5’ direction and channels mRNA to the cytosolic exosome for degradation. SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling. In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C).

Subunit / interactions. Component of the SKI complex which consists of SKIC2, SKIC3 and SKIC8. Interacts with PAF1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with the highest levels observed in vascular tissues, lymph node, pituitary, lung and intestine. Not expressed in the liver.

Disease relevance. Trichohepatoenteric syndrome 1 (THES1) [MIM:222470] A syndrome characterized by intrauterine growth retardation, severe diarrhea in infancy requiring total parenteral nutrition, facial dysmorphism, immunodeficiency, and hair abnormalities, mostly trichorrhexis nodosa. Hepatic involvement contributes to the poor prognosis of affected patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SKI3 family.

RefSeq proteins (1): NP_055454* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR039226	Ski3/TTC37	Family

Pfam: PF13181, PF13432, PF14559

UniProt features (111 total): helix 65, repeat 20, strand 11, sequence variant 9, turn 3, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
7QDY	ELECTRON MICROSCOPY	3.1
9G8O	ELECTRON MICROSCOPY	3.4
9G8R	ELECTRON MICROSCOPY	3.4
7QDZ	ELECTRON MICROSCOPY	3.6
7QDR	ELECTRON MICROSCOPY	3.7
7QDS	ELECTRON MICROSCOPY	3.8
9G8Q	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PGP7-F1	86.17	0.39

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-429914	Deadenylation-dependent mRNA decay
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 356 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, TGCGCANK_UNKNOWN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TRANSLATION, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, GOBP_TRANSLATIONAL_ELONGATION, SENESE_HDAC1_TARGETS_UP, GOBP_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_NONSENSE_MEDIATED_DECAY, ACEVEDO_LIVER_CANCER_UP, GOBP_ORGANELLE_DISASSEMBLY, chr5q15, REACTOME_METABOLISM_OF_RNA, SANSOM_APC_MYC_TARGETS, GOCC_EUCHROMATIN

GO Biological Process (4): nuclear-transcribed mRNA catabolic process (GO:0000956), nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay (GO:0070478), rescue of stalled cytosolic ribosome (GO:0072344), RNA catabolic process (GO:0006401)

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

GO Cellular Component (6): euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), Ski complex (GO:0055087)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
mRNA catabolic process	1
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1
cytoplasmic translational elongation	1
ribosome disassembly	1
RNA metabolic process	1
nucleic acid catabolic process	1
binding	1
chromatin	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1617 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SKIC3	SKIC2	Q15477	998
SKIC3	SKIC8	Q9GZS3	998
SKIC3	EXOSC10	Q01780	824
SKIC3	EXOSC1	Q9Y3B2	747
SKIC3	MTREX	P42285	746
SKIC3	XRN1	Q8IZH2	713
SKIC3	HBS1L	Q9Y450	711
SKIC3	TTC7A	Q9ULT0	667
SKIC3	EXOSC4	Q9NPD3	666
SKIC3	EXOSC3	Q9NQT5	648
SKIC3	EXOSC6	Q5RKV6	632
SKIC3	DIS3	Q9Y2L1	627
SKIC3	EXOSC7	Q15024	623
SKIC3	EXOSC5	Q9NQT4	622
SKIC3	ZCCHC7	Q8N3Z6	618

IntAct

74 interactions, top by confidence:

A	B	Type	Score
SKIC8	SKIC2	psi-mi:“MI:0914”(association)	0.710
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
SKIC8	PFDN6	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
SKIC3	PAF1	psi-mi:“MI:0915”(physical association)	0.520
PAF1	SKIC3	psi-mi:“MI:0915”(physical association)	0.520
SKIC3	IMMT	psi-mi:“MI:0915”(physical association)	0.400
SKIC3	OGDH	psi-mi:“MI:0915”(physical association)	0.400
SKIC3	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
SKIC3	NS1	psi-mi:“MI:0915”(physical association)	0.400
SKIC3	ORF4a	psi-mi:“MI:0915”(physical association)	0.400
SKIC2	SKIC3	psi-mi:“MI:0915”(physical association)	0.400
PCNA	SKIC3	psi-mi:“MI:0915”(physical association)	0.370
SMAD9	SKIC3	psi-mi:“MI:0915”(physical association)	0.370
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Spcs2	SEC11A	psi-mi:“MI:0914”(association)	0.350
Eif3a	RPSA	psi-mi:“MI:0914”(association)	0.350
Skic8	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350
Rrbp1	PIPSL	psi-mi:“MI:0914”(association)	0.350
HNRNPU		psi-mi:“MI:0914”(association)	0.350
NPM1	RPSA	psi-mi:“MI:0914”(association)	0.350
CEP162	IPO5	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NEURL4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350

BioGRID (138): TTC37 (Affinity Capture-MS), TTC37 (Affinity Capture-MS), TTC37 (Affinity Capture-MS), TLN1 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Co-fractionation), TTC37 (Affinity Capture-MS), TTC37 (Affinity Capture-MS), TTC37 (Affinity Capture-MS), TTC37 (Affinity Capture-MS)

ESM2 similar proteins: A1A4R8, B0BNG0, B3DNN5, E7F590, F8VPK0, O89079, P45432, P49754, P62944, P63009, P63010, Q12996, Q15006, Q28G25, Q2KJ25, Q4QR29, Q5E993, Q5F3K0, Q5KU39, Q5M7J9, Q5R4J9, Q5R882, Q5RBI3, Q5RDW9, Q60445, Q62018, Q6DEU9, Q6DFB8, Q6INS3, Q6N069, Q6PD62, Q6PGP7, Q6TGY8, Q80UM3, Q8AVU9, Q8BGZ4, Q8TAM2, Q8VD72, Q8VY89, Q8VZM1

Diamond homologs: F8VPK0, P17883, Q6DFB8, Q6PGP7, P35056, Q6CT48, Q6FM42, Q752X0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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
Influenza Viral RNA Transcription and Replication	5	16.6×	3e-03
Influenza Infection	5	13.5×	3e-03
SARS-CoV-1-host interactions	5	13.5×	3e-03
rRNA processing in the nucleus and cytosol	5	12.4×	3e-03
rRNA processing	5	11.3×	4e-03
Peptide chain elongation	5	9.8×	5e-03
Viral mRNA Translation	5	9.8×	5e-03
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	5	9.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	6	12.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1622 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	119
Likely pathogenic	56
Uncertain significance	482
Likely benign	802
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069367	NM_014639.4(SKIC3):c.357C>A (p.Cys119Ter)	Pathogenic
1076047	NM_014639.4(SKIC3):c.1808C>A (p.Ser603Ter)	Pathogenic
1402735	NM_014639.4(SKIC3):c.1029dup (p.Asn344Ter)	Pathogenic
1411993	NM_014639.4(SKIC3):c.949del (p.Val317fs)	Pathogenic
1413550	NM_014639.4(SKIC3):c.1762C>T (p.Gln588Ter)	Pathogenic
1415105	NM_014639.4(SKIC3):c.1159G>T (p.Gly387Ter)	Pathogenic
1419394	NM_014639.4(SKIC3):c.2092A>T (p.Lys698Ter)	Pathogenic
1420461	NM_014639.4(SKIC3):c.1924C>T (p.Gln642Ter)	Pathogenic
1456349	NM_014639.4(SKIC3):c.860del (p.Lys287fs)	Pathogenic
1456844	NM_014639.4(SKIC3):c.113dup (p.Asn38fs)	Pathogenic
1458865	NC_000005.9:g.(?94877499)(94882854_?)del	Pathogenic
1459058	NM_014639.4(SKIC3):c.1708C>T (p.Arg570Ter)	Pathogenic
1686282	NM_014639.4(SKIC3):c.2849_2850del (p.Glu950fs)	Pathogenic
1708563	NM_014639.4(SKIC3):c.4102C>T (p.Gln1368Ter)	Pathogenic
1896207	NM_014639.4(SKIC3):c.2921-1G>A	Pathogenic
1914735	NM_014639.4(SKIC3):c.744del (p.Ile248fs)	Pathogenic
1937724	NM_014639.4(SKIC3):c.3221_3222del (p.Ala1073_Tyr1074insTer)	Pathogenic
196135	NM_014639.4(SKIC3):c.2808G>A (p.Trp936Ter)	Pathogenic
1965292	NM_014639.4(SKIC3):c.60_63del (p.Lys20fs)	Pathogenic
2027944	NM_014639.4(SKIC3):c.3877C>T (p.Gln1293Ter)	Pathogenic
2074735	NM_014639.4(SKIC3):c.408_418del (p.Arg137fs)	Pathogenic
2100603	NM_014639.4(SKIC3):c.1927C>T (p.Gln643Ter)	Pathogenic
2182515	NM_014639.4(SKIC3):c.3731dup (p.Ser1245fs)	Pathogenic
2203665	NM_014639.4(SKIC3):c.1305dup (p.Tyr436fs)	Pathogenic
2425959	NC_000005.9:g.(?94820408)(94820569_?)del	Pathogenic
2498975	NM_014639.4(SKIC3):c.85del (p.Cys29fs)	Pathogenic
2655594	NM_014639.4(SKIC3):c.3850_3854del (p.Asp1284fs)	Pathogenic
2697932	NM_014639.4(SKIC3):c.3772_3784dup (p.Ala1262fs)	Pathogenic
2709015	NM_014639.4(SKIC3):c.1610del (p.Leu537fs)	Pathogenic
2712632	NM_014639.4(SKIC3):c.1186del (p.Tyr396fs)	Pathogenic

SpliceAI

6211 predictions. Top by Δscore:

Variant	Effect	Δscore
5:95467860:CCTTA:C	donor_loss	1.0000
5:95467861:CTTAC:C	donor_loss	1.0000
5:95467862:TTA:T	donor_loss	1.0000
5:95467863:TACGT:T	donor_loss	1.0000
5:95467864:A:AC	donor_gain	1.0000
5:95467865:C:CC	donor_gain	1.0000
5:95467865:CGT:C	donor_gain	1.0000
5:95467986:CTCT:C	acceptor_gain	1.0000
5:95467988:CT:C	acceptor_gain	1.0000
5:95467989:TC:T	acceptor_loss	1.0000
5:95467990:C:CC	acceptor_gain	1.0000
5:95467991:T:C	acceptor_loss	1.0000
5:95478289:CCATA:C	donor_gain	1.0000
5:95478294:CAGA:C	donor_gain	1.0000
5:95478440:CCA:C	acceptor_gain	1.0000
5:95478441:CA:C	acceptor_gain	1.0000
5:95478441:CAC:C	acceptor_gain	1.0000
5:95478442:AC:A	acceptor_loss	1.0000
5:95478443:C:CC	acceptor_gain	1.0000
5:95478443:CTAAG:C	acceptor_loss	1.0000
5:95482468:CTTA:C	donor_loss	1.0000
5:95482470:TA:T	donor_loss	1.0000
5:95482471:A:AC	donor_gain	1.0000
5:95482471:A:T	donor_loss	1.0000
5:95482471:ACCTG:A	donor_gain	1.0000
5:95482472:C:CC	donor_gain	1.0000
5:95482472:CCTG:C	donor_gain	1.0000
5:95482472:CCTGC:C	donor_gain	1.0000
5:95482630:TT:T	acceptor_gain	1.0000
5:95482632:C:CC	acceptor_gain	1.0000

AlphaMissense

10215 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:95543221:G:T	A66D	0.999
5:95543278:C:T	G47D	0.999
5:95543279:C:G	G47R	0.999
5:95547105:C:G	A16P	0.999
5:95547113:G:T	A13D	0.999
5:95541906:C:G	G79R	0.998
5:95541906:C:T	G79R	0.998
5:95543191:G:T	A76D	0.998
5:95543222:C:G	A66P	0.998
5:95543270:C:G	A50P	0.998
5:95543272:G:T	A49D	0.998
5:95543287:A:T	V44D	0.998
5:95543293:G:T	A42D	0.998
5:95547064:A:C	C29W	0.998
5:95547066:A:G	C29R	0.998
5:95547122:A:G	L10P	0.998
5:95514866:A:G	W898R	0.997
5:95514866:A:T	W898R	0.997
5:95516692:C:T	G832D	0.997
5:95541833:A:G	L103P	0.997
5:95543231:A:C	Y63D	0.997
5:95543242:G:T	A59D	0.997
5:95543243:C:G	A59P	0.997
5:95543273:C:G	A49P	0.997
5:95547065:C:T	C29Y	0.997
5:95547114:C:G	A13P	0.997
5:95513645:C:G	A902P	0.996
5:95514864:C:A	W898C	0.996
5:95514864:C:G	W898C	0.996
5:95516384:C:T	G868E	0.996

dbSNP variants (sampled 300 via entrez): RS1000016977 (5:95494441 T>C), RS1000093461 (5:95555405 G>A,C,T), RS1000128826 (5:95538890 C>A,T), RS1000167440 (5:95515413 T>C), RS1000217426 (5:95485596 G>A), RS1000222026 (5:95496017 T>A,C), RS1000262816 (5:95470633 T>C), RS1000273256 (5:95480212 A>G), RS1000302772 (5:95515098 T>C), RS1000329608 (5:95522532 T>G), RS1000361709 (5:95477179 T>C), RS1000373824 (5:95473793 A>C), RS1000386221 (5:95529952 C>T), RS1000391219 (5:95476863 T>C), RS1000458296 (5:95508711 G>A)

Disease associations

OMIM: gene MIM:614589 | disease phenotypes: MIM:222470

GenCC curated gene-disease

Disease	Classification	Inheritance
trichohepatoenteric syndrome 1	Definitive	Autosomal recessive
trichohepatoenteric syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
trichohepatoenteric syndrome 1	Definitive	AR

Mondo (3): trichohepatoenteric syndrome 1 (MONDO:0024541), trichohepatoenteric syndrome (MONDO:0009105), prostate cancer (MONDO:0008315)

Orphanet (2): Trichohepatoenteric syndrome (Orphanet:84064), Familial prostate cancer (Orphanet:1331)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000047	Hypospadias
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000445	Wide nose
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000520	Proptosis
HP:0000778	Hypoplasia of the thymus
HP:0000821	Hypothyroidism
HP:0000952	Jaundice
HP:0000957	Cafe-au-lait spot
HP:0000958	Dry skin
HP:0001194	Abnormalities of placenta or umbilical cord
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006485_3	Telomere length	2.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067288 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12657120	Efficacy	3	duloxetine	Major Depressive Disorder
rs4639250	Efficacy	3	duloxetine	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12657120	SKIC3	3	0.00	1	duloxetine
rs4639250	SKIC3	3	0.00	1	duloxetine

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.36	Kd	4.399	nM	CHEMBL5653589
8.36	ED50	4.399	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149668: Binding affinity to human TTC37 incubated for 45 mins by Kinobead based pull down assay	kd	0.0044	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
testosterone undecanoate	decreases expression, affects cotreatment	1
trichostatin A	decreases expression	1
tetrahydropalmatine	decreases expression	1
arsenite	decreases reaction, affects binding	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Diethylstilbestrol	increases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1
Silicon Dioxide	decreases expression	1
Theophylline	decreases expression	1
Thimerosal	decreases expression	1
Vanadates	increases 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
CHEMBL5652710	Binding	Binding affinity to human TTC37 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer