NPAT

Summary

NPAT (nuclear protein, coactivator of histone transcription, HGNC:7896) is a protein-coding gene on chromosome 11q22.3, encoding Protein NPAT (Q14207). Transcription regulator required for progression through the G1 and S phases of the cell cycle and for S phase entry. It is a selective cancer dependency (DepMap: 89.7% of cell lines).

Enables transcription coactivator activity and transcription corepressor activity. Involved in cell cycle G1/S phase transition and positive regulation of transcription by RNA polymerase II. Located in Cajal body; Gemini of Cajal bodies; and cytoplasm.

Source: NCBI Gene 4863 — RefSeq curated summary.

At a glance

• Gene–disease (curated): colorectal cancer (Limited, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 2,352 total
• Phenotypes (HPO): 53
• Cancer dependency (DepMap): dependent in 89.7% of screened cell lines
• MANE Select transcript: NM_002519

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7896
Approved symbol	NPAT
Name	nuclear protein, coactivator of histone transcription
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	E14, p220
Ensembl gene	ENSG00000149308
Ensembl biotype	protein_coding
OMIM	601448
Entrez	4863

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000278612, ENST00000527296, ENST00000530859, ENST00000530926, ENST00000531384, ENST00000610253, ENST00000850623, ENST00000935790

RefSeq mRNA: 2 — MANE Select: NM_002519 NM_001321307, NM_002519

CCDS: CCDS41710

Canonical transcript exons

ENST00000278612 — 18 exons

Exon	Start	End
ENSE00000989905	108189106	108189330
ENSE00001101688	108169928	108170043
ENSE00001101716	108172199	108173851
ENSE00002170827	108222500	108222638
ENSE00003481381	108185232	108185319
ENSE00003490868	108185403	108185494
ENSE00003508823	108197302	108197420
ENSE00003520638	108193957	108194017
ENSE00003524830	108186482	108186569
ENSE00003535531	108169744	108169852
ENSE00003540993	108176994	108177090
ENSE00003543369	108176246	108176374
ENSE00003562597	108160880	108162014
ENSE00003626306	108192118	108192190
ENSE00003659402	108188098	108188179
ENSE00003663181	108162120	108162180
ENSE00003677327	108190460	108190500
ENSE00004282360	108157215	108159019

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1508 / max 254.2249, expressed in 1798 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122140	22.1508	1798

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.22	gold quality
calcaneal tendon	UBERON:0003701	91.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.88	gold quality
endothelial cell	CL:0000115	89.16	gold quality
visceral pleura	UBERON:0002401	88.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.64	gold quality
parietal pleura	UBERON:0002400	88.39	gold quality
pleura	UBERON:0000977	88.04	gold quality
oocyte	CL:0000023	86.30	gold quality
colonic epithelium	UBERON:0000397	85.67	gold quality
tibia	UBERON:0000979	85.16	gold quality
tonsil	UBERON:0002372	85.16	gold quality
ventricular zone	UBERON:0003053	84.93	gold quality
bone marrow cell	CL:0002092	84.89	gold quality
germinal epithelium of ovary	UBERON:0001304	83.97	gold quality
ganglionic eminence	UBERON:0004023	83.82	gold quality
cauda epididymis	UBERON:0004360	83.76	gold quality
palpebral conjunctiva	UBERON:0001812	83.75	gold quality
adrenal tissue	UBERON:0018303	83.71	gold quality
epithelial cell of pancreas	CL:0000083	83.12	gold quality
amniotic fluid	UBERON:0000173	83.06	gold quality
epithelium of nasopharynx	UBERON:0001951	82.89	gold quality
nasopharynx	UBERON:0001728	82.87	gold quality
esophagus squamous epithelium	UBERON:0006920	82.83	gold quality
lymph node	UBERON:0000029	82.74	gold quality
choroid plexus epithelium	UBERON:0003911	82.68	gold quality
upper leg skin	UBERON:0004262	82.65	gold quality
blood	UBERON:0000178	82.62	gold quality
corpus epididymis	UBERON:0004359	81.96	gold quality
bone marrow	UBERON:0002371	81.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, E2F1, E2F2, E2F3, E2F4, HES1, HINFP, STAT1, TP53

miRNA regulators (miRDB)

139 targeting NPAT, 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-432-3P	100.00	67.86	705
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-10523-5P	99.91	69.22	2038

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 89.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 20)

• Results characterize the functional signals required for NPAT localization to the cell nucleus. (PMID:12473189)
• NPAT links E2F to the activation of S-phase-specific histone gene transcription. (PMID:12665581)
• the ability of p220 to promote S phase is independent of its ability to promote histone H4 transcription and p220 may link cyclin E/Cdk2 to multiple independent downstream functions (PMID:12724424)
• OCA-S, the multicomponent Oct-1 coactivator, intercts with NPAT. (PMID:12887926)
• p220 is an essential downstream component of the cyclin E/Cdk2 signaling pathway and functions to coordinate multiple elements of the G1/S transition. (PMID:14612403)
• NPAT, together with CUL5 and PPP2R1B, is implicated in the deregulation of the cell-cycle and apoptosis regulators and in the pathogenesis of B-CLL. (PMID:17449237)
• NPAT recruits the TRRAP-Tip60 complex to histone gene promoters to coordinate the transcriptional activation of multiple histone genes during the G(1)/S-phase transition (PMID:17967892)
• HiNF-P/P220NPAT regulates expression of nonhistone targets that influence competency for cell cycle progression. (PMID:17974976)
• Only the number of FLASH/NPAT histone gene locus bodies correlates with ploidy and only these organelles appear to be regulated during the cell cycle. (PMID:18677100)
• Results suggest that cyclin-dependent kinase inhibitors selectively control stimulation of the histone H4 gene promoter by the p220(NPAT)/HiNF-P complex. (PMID:19170105)
• The subnuclear organization of histone gene regulatory proteins and 3’ end processing factors (NPAT/LSM10) of normal somatic and embryonic stem cells is compromised in selected human cancer cell types. (PMID:19277982)
• Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells. (PMID:19890848)
• NPAT is essential for histone mRNA 3’ end processing and recruits CDK9 to replication-dependent histone genes. (PMID:20190802)
• Genetic variants of NPAT-ATM and AURKA are associated with an individual early adverse reaction in the gastrointestinal tract of patients with cervical cancer treated with pelvic radiation therapy (PMID:21050672)
• NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition. (PMID:21562039)
• The conserved C-terminal domain shared by FLASH, YARP, and Mute recognizes the C-terminal sequence of NPAT orthologues, thus acting as a signal targeting proteins to histone locus bodies. (PMID:25339177)
• Cpn10 has a role in the spatial regulation of NPAT signaling (PMID:26429916)
• Structural Analysis of the SANT/Myb Domain of FLASH and YARP Proteins and Their Complex with the C-Terminal Fragment of NPAT by NMR Spectroscopy and Computer Simulations. (PMID:32722282)
• The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection. (PMID:34197485)
• Germline NPAT inactivating variants as cause of hereditary colorectal cancer. (PMID:38778081)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	npat	ENSDARG00000055548
mus_musculus	Npat	ENSMUSG00000033054
rattus_norvegicus	Npat	ENSRNOG00000024934

Protein

Protein identifiers

Protein NPAT — Q14207 (reviewed: Q14207)

Alternative names: Nuclear protein of the ataxia telangiectasia mutated locus, p220

All UniProt accessions (3): Q14207, E9PKJ1, H0YET3

UniProt curated annotations — full annotation on UniProt →

Function. Transcription regulator required for progression through the G1 and S phases of the cell cycle and for S phase entry. Acts as a key transcription regulator of histones. Activates transcription of the histone H2A, histone H2B, histone H3 and histone H4 genes in conjunction with GON4L and MIZF. Together with CRAMP1, binds to the promoters of H1 genes (H1-2, H1-3, H1-4, H1-5 and H1-10/H1x), driving their transcription. Also positively regulates the ATM, MIZF and PRKDC promoters. Transcriptional activation may be accomplished at least in part by the recruitment of the NuA4 histone acetyltransferase (HAT) complex to target gene promoters.

Subunit / interactions. Interacts with the cylin/CDK complexes CCNE1/CDK2 and CCNA1/CDK2. Interacts with BZW1, CASP8AP2, CREBBP, MIZF and YY1. Interacts with the RUVBL1, RUVBL2 and TRRAP subunits of the NuA4 complex. May also interact with GAPDH, NME1, NME2 and STIP1. Interacts with GON4L. Interacts with CRAMP1; promoting CRAMP1 recruitment to histone locus bodies (HLB).

Subcellular location. Nucleus. Cajal body. Chromosome.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated at Ser-775, Ser-779, Ser-1100, Thr-1270 and Thr-1350 by CCNE1/CDK2 at G1-S transition and until prophase, which promotes association with histone gene clusters and stimulates activation of histone transcription. Also phosphorylated by CCNA1/CDK2 in vitro.

Domain organisation. The LisH domain is required for the activation of histone gene transcription.

Induction. By expression of E2F1, E2F2, E2F3 and E2F4. Expression is reduced in response to radiation-induced DNA damage.

Similarity. Belongs to the NPAT family.

RefSeq proteins (2): NP_001308236, NP_002510* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006594	LisH	Conserved_site
IPR031442	NPAT_C	Domain
IPR052850	NPAT_LisH	Family

Pfam: PF15712

UniProt features (76 total): region of interest 16, sequence variant 13, mutagenesis site 13, modified residue 12, compositionally biased region 11, sequence conflict 6, cross-link 3, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14207-F1	44.62	0.03

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 (15): 207, 554, 599, 775, 779, 1100, 1151, 1200, 1228, 1254, 1270, 1350, 1116, 1149, 1280

Mutagenesis-validated functional residues (13):

Position	Phenotype
7	impairs activation of histone gene transcription; when associated with a-10; a-11; a-15 and a-18.
10	impairs activation of histone gene transcription; when associated with a-7; a-11; a-15 and a-18.
11	impairs activation of histone gene transcription; when associated with a-7; a-10; a-15 and a-18.
15	impairs activation of histone gene transcription; when associated with a-7; a-10; a-11 and a-18.
18	impairs activation of histone gene transcription; when associated with a-7; a-10; a-11 and a-15.
27	impairs activation of histone gene transcription; when associated with a-30.
30	impairs activation of histone gene transcription; when associated with a-27.
331–333	impairs activation of histone gene transcription. impairs interaction with bzw1, ruvbl1, ruvbl2 and trrap.
775	impairs activation of histone gene transcription; when associated with a-779; a-1100; a-1270 and a-1350.
779	impairs activation of histone gene transcription; when associated with a-775; a-1100; a-1270 and a-1350.
1100	impairs activation of histone gene transcription; when associated with a-775; a-779; a-1270 and a-1350.
1270	impairs activation of histone gene transcription; when associated with a-775; a-779; a-1100 and a-1350.
1350	impairs activation of histone gene transcription; when associated with a-775; a-779; a-1100 and a-1270.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 333 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, FISCHER_G1_S_CELL_CYCLE, TGCACTT_MIR519C_MIR519B_MIR519A, chr11q22, GOBP_CELL_CYCLE_PHASE_TRANSITION, GTGCCTT_MIR506, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, FISCHER_DREAM_TARGETS, ACTTTAT_MIR1425P, GOBP_EMBRYO_DEVELOPMENT, YIH_RESPONSE_TO_ARSENITE_C4, VERNELL_RETINOBLASTOMA_PATHWAY_UP

GO Biological Process (5): in utero embryonic development (GO:0001701), cell cycle G1/S phase transition (GO:0044843), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (4): transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Cajal body (GO:0015030), Gemini of Cajal bodies (GO:0097504)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
regulation of DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
transcription coregulator activity	2
cellular anatomical structure	2
chordate embryonic development	1
cell cycle phase transition	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of RNA biosynthetic process	1
transcription regulator activity	1
negative regulation of DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
nuclear body	1

Protein interactions and networks

STRING

1958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPAT	LSM11	P83369	874
NPAT	CDK2	P24941	847
NPAT	CASP8AP2	Q9UKL3	819
NPAT	ACAT1	P24752	810
NPAT	HINFP	Q9BQA5	729
NPAT	TRRAP	Q9Y4A5	728
NPAT	COIL	P38432	722
NPAT	LSM10	Q969L4	715
NPAT	CPSF3	Q9UKF6	703
NPAT	ATM	Q13315	654
NPAT	GAPDH	P00354	652
NPAT	H4C7	Q99525	625
NPAT	H2BC21	Q16778	622
NPAT	H4C16	P02304	616
NPAT	SLBP	Q14493	589

IntAct

57 interactions, top by confidence:

A	B	Type	Score
RBBP7	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
RBBP7	HAT1	psi-mi:“MI:0914”(association)	0.730
ZNF219	CDK2AP1	psi-mi:“MI:0914”(association)	0.640
ASB7	POLR3A	psi-mi:“MI:0914”(association)	0.530
CRAMP1	NPAT	psi-mi:“MI:0914”(association)	0.530
H2BC26	PPM1G	psi-mi:“MI:0914”(association)	0.530
RBBP4	TNRC18	psi-mi:“MI:0914”(association)	0.530
RBBP7	SMARCA5	psi-mi:“MI:0914”(association)	0.530
HCCS	NPAT	psi-mi:“MI:0914”(association)	0.530
NPAT		psi-mi:“MI:0915”(physical association)	0.520
CASP8AP2	NPAT	psi-mi:“MI:0915”(physical association)	0.400
NPAT	WEE1	psi-mi:“MI:0915”(physical association)	0.400
RNF41	CLEC16A	psi-mi:“MI:0914”(association)	0.350
Gspt1	MRPL27	psi-mi:“MI:0914”(association)	0.350
Dut	NPAT	psi-mi:“MI:0914”(association)	0.350
GAR1	TAF1	psi-mi:“MI:0914”(association)	0.350
LTN1	KIF2A	psi-mi:“MI:0914”(association)	0.350
AP4M1		psi-mi:“MI:0914”(association)	0.350
S100A4	BBX	psi-mi:“MI:0914”(association)	0.350
H4C16		psi-mi:“MI:0914”(association)	0.350
HCCS	MPZL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (108): NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-RNA), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS), NPAT (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GSA2, A0A1L8H0H2, A0JP82, A0MS83, A2AWL7, A2RRX6, A2X0Q0, A6NCI8, A9ZPC9, F8VPJ6, K9JHZ4, O13186, O46567, O60284, O75362, P15822, P35547, P37275, P48552, P52551, P79269, Q03172, Q14207, Q28DZ0, Q2KHR2, Q3V0A6, Q3Y4E1, Q4JK59, Q4V7J0, Q5DTW7, Q5R782, Q5W1J6, Q5ZJK5, Q61624, Q62806, Q6N021, Q6YXZ4, Q7SZL5, Q80TY4, Q8BMA5

Diamond homologs: A2RRX6, Q14207, Q8BMA5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CDK2	up-regulates	NPAT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 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
Deposition of new CENPA-containing nucleosomes at the centromere	8	28.2×	8e-08
NuRD complex assembly	7	21.9×	4e-06
Defective pyroptosis	6	20.9×	2e-05
PRC2 methylates histones and DNA	6	20.3×	2e-05
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	6	20.3×	2e-05
Interaction of NuRD complexes with transcription factors	7	19.7×	5e-06
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	16.3×	3e-04
Negative Regulation of CDH1 Gene Transcription	6	16.0×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	6	14.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2352 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1521
Likely benign	750
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

2687 predictions. Top by Δscore:

Variant	Effect	Δscore
11:108162118:A:AC	donor_gain	1.0000
11:108162119:C:CC	donor_gain	1.0000
11:108169749:CAAGG:C	donor_gain	1.0000
11:108169764:AGT:A	donor_gain	1.0000
11:108169764:AGTC:A	donor_gain	1.0000
11:108169814:T:TA	donor_gain	1.0000
11:108170044:C:CC	acceptor_gain	1.0000
11:108176989:CTT:C	donor_loss	1.0000
11:108176990:TTACC:T	donor_loss	1.0000
11:108176991:TAC:T	donor_loss	1.0000
11:108176992:A:AC	donor_gain	1.0000
11:108176992:A:T	donor_loss	1.0000
11:108176993:C:CA	donor_loss	1.0000
11:108176993:C:CC	donor_gain	1.0000
11:108177086:TCACT:T	acceptor_gain	1.0000
11:108177087:CACT:C	acceptor_gain	1.0000
11:108177087:CACTC:C	acceptor_gain	1.0000
11:108177088:ACT:A	acceptor_gain	1.0000
11:108177088:ACTC:A	acceptor_loss	1.0000
11:108177089:CT:C	acceptor_gain	1.0000
11:108177089:CTC:C	acceptor_gain	1.0000
11:108177090:TC:T	acceptor_loss	1.0000
11:108177090:TCT:T	acceptor_gain	1.0000
11:108177091:C:CC	acceptor_gain	1.0000
11:108177091:C:CG	acceptor_loss	1.0000
11:108177092:T:G	acceptor_loss	1.0000
11:108185226:CCATA:C	donor_loss	1.0000
11:108185227:CATA:C	donor_loss	1.0000
11:108185229:TACC:T	donor_loss	1.0000
11:108185230:A:AC	donor_gain	1.0000

AlphaMissense

9379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:108158970:A:G	F1419S	1.000
11:108185433:A:G	L263P	1.000
11:108158969:A:C	F1419L	0.999
11:108158969:A:T	F1419L	0.999
11:108158971:A:G	F1419L	0.999
11:108161073:A:G	L1338P	0.999
11:108177022:A:C	F325L	0.999
11:108177022:A:T	F325L	0.999
11:108177024:A:G	F325L	0.999
11:108177053:A:T	I315K	0.999
11:108185472:C:G	R250P	0.999
11:108192130:A:G	L93P	0.999
11:108197357:A:G	L34S	0.999
11:108222508:A:G	L10P	0.999
11:108158967:A:G	L1420S	0.998
11:108158970:A:C	F1419C	0.998
11:108161073:A:T	L1338H	0.998
11:108161082:A:G	L1335S	0.998
11:108172765:A:G	L740P	0.998
11:108177014:A:G	L328P	0.998
11:108177023:A:G	F325S	0.998
11:108177053:A:C	I315R	0.998
11:108185431:C:G	A264P	0.998
11:108185433:A:T	L263Q	0.998
11:108185460:A:G	L254P	0.998
11:108185463:A:G	I253T	0.998
11:108185463:A:T	I253K	0.998
11:108185476:C:G	A249P	0.998
11:108192142:A:G	L89S	0.998
11:108192152:A:G	W86R	0.998

dbSNP variants (sampled 300 via entrez): RS1000005768 (11:108222901 C>G,T), RS1000006299 (11:108169326 G>A), RS1000094754 (11:108214663 G>A), RS1000128469 (11:108183945 G>A), RS1000147521 (11:108175352 G>A), RS1000258854 (11:108224033 A>T), RS1000258861 (11:108166373 C>CA), RS1000321447 (11:108207630 G>A,C), RS1000357296 (11:108212322 C>T), RS1000364183 (11:108169203 G>A), RS1000366482 (11:108175695 G>A), RS1000421585 (11:108217966 T>C,G), RS1000459675 (11:108184221 G>A), RS1000474814 (11:108201826 C>T), RS1000503277 (11:108197054 C>G)

Disease associations

OMIM: gene MIM:601448 | disease phenotypes: MIM:208900

GenCC curated gene-disease

Disease	Classification	Inheritance
colorectal cancer	Limited	Autosomal dominant

Mondo (3): familial colorectal cancer type X (MONDO:0018604), ataxia telangiectasia (MONDO:0008840), colorectal cancer (MONDO:0005575)

Orphanet (2): Familial colorectal cancer Type X (Orphanet:440437), Ataxia-telangiectasia (Orphanet:100)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000505	Visual impairment
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001371	Flexion contracture
HP:0001402	Hepatocellular carcinoma
HP:0001824	Weight loss
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002076	Migraine
HP:0002167	Abnormal speech pattern
HP:0002239	Gastrointestinal hemorrhage
HP:0002354	Memory impairment
HP:0002376	Developmental regression
HP:0002516	Increased intracranial pressure
HP:0002671	Basal cell carcinoma
HP:0002893	Pituitary adenoma
HP:0002894	Neoplasm of the pancreas
HP:0003006	Neuroblastoma
HP:0003401	Paresthesia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004607_131	Plateletcrit	1.000000e-26
GCST007250_11	Nonunion in individuals with fractures	3.000000e-07
GCST009375_13	Mosaic loss of chromosome Y (Y chromosome dosage)	7.000000e-11
GCST010002_248	Refractive error	4.000000e-19
GCST90002389_369	Lymphocyte percentage of white cells	2.000000e-13
GCST90002393_440	Monocyte count	2.000000e-14
GCST90002397_539	Mean spheric corpuscular volume	7.000000e-27
GCST90002402_387	Platelet count	5.000000e-21

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0009707	fractures, ununited
EFO:0007783	mosaic loss of chromosome Y measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001260	Ataxia Telangiectasia	C10.228.140.252.190.530.060; C10.562.100; C10.597.350.090.500.530.060; C14.907.823.213; C16.320.080; C16.320.798.250; C18.452.284.060; C20.673.795.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, decreases expression	3
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Clorgyline	increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases oxidation, increases abundance, affects cotreatment	1
Thimerosal	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer