AHRR

Summary

AHRR (aryl hydrocarbon receptor repressor, HGNC:346) is a protein-coding gene on chromosome 5p15.33, encoding Aryl hydrocarbon receptor repressor (A9YTQ3). Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation.

The protein encoded by this gene participates in the aryl hydrocarbon receptor (AhR) signaling cascade, which mediates dioxin toxicity, and is involved in regulation of cell growth and differentiation. It functions as a feedback modulator by repressing AhR-dependent gene expression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 57491 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 216 total — 19 pathogenic
• MANE Select transcript: NM_001377236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:346
Approved symbol	AHRR
Name	aryl hydrocarbon receptor repressor
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1234, bHLHe77
Ensembl gene	ENSG00000063438
Ensembl biotype	protein_coding
OMIM	606517
Entrez	57491

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 retained_intron

ENST00000316418, ENST00000504625, ENST00000506456, ENST00000507048, ENST00000510400, ENST00000510910, ENST00000511487, ENST00000514523, ENST00000515206, ENST00000652417, ENST00000684583, ENST00000911400, ENST00000949535

RefSeq mRNA: 2 — MANE Select: NM_001377236 NM_001377236, NM_001377239

CCDS: CCDS93682

Canonical transcript exons

ENST00000684583 — 11 exons

Exon	Start	End
ENSE00003904847	422729	422858
ENSE00003905662	376610	376716
ENSE00003905820	343893	343964
ENSE00003906347	432463	432524
ENSE00003909161	413344	413433
ENSE00003909175	432806	432947
ENSE00003909735	353730	353911
ENSE00003909813	427807	428006
ENSE00003909928	423841	423977
ENSE00003916936	433853	438285
ENSE00003917120	321714	321819

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 87.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9982 / max 127.5040, expressed in 1053 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55467	7.8567	1050
55469	0.0853	31
55468	0.0362	5
55479	0.0200	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	87.93	gold quality
stromal cell of endometrium	CL:0002255	87.83	gold quality
right testis	UBERON:0004534	87.16	gold quality
testis	UBERON:0000473	86.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.13	gold quality
spleen	UBERON:0002106	74.51	gold quality
colonic epithelium	UBERON:0000397	72.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.11	gold quality
lower esophagus mucosa	UBERON:0035834	71.40	gold quality
skin of leg	UBERON:0001511	70.08	gold quality
mucosa of transverse colon	UBERON:0004991	69.97	gold quality
zone of skin	UBERON:0000014	69.68	gold quality
superior frontal gyrus	UBERON:0002661	68.97	gold quality
skin of abdomen	UBERON:0001416	68.89	gold quality
esophagus mucosa	UBERON:0002469	67.46	gold quality
vagina	UBERON:0000996	66.64	gold quality
placenta	UBERON:0001987	66.18	gold quality
prefrontal cortex	UBERON:0000451	66.04	gold quality
frontal cortex	UBERON:0001870	65.95	gold quality
right frontal lobe	UBERON:0002810	65.83	gold quality
anterior cingulate cortex	UBERON:0009835	65.76	gold quality
islet of Langerhans	UBERON:0000006	65.51	gold quality
ectocervix	UBERON:0012249	65.32	gold quality
gall bladder	UBERON:0002110	64.97	gold quality
urinary bladder	UBERON:0001255	64.90	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	64.70	gold quality
left ovary	UBERON:0002119	64.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.59	gold quality
cerebral cortex	UBERON:0000956	64.49	gold quality
right ovary	UBERON:0002118	64.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ENAD-27	no	3.61
E-ANND-3	no	1.87

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
AHR	Repression
AHRR
ARNT	Repression
CYP1A1
CYP1A2	Activation
MYC	Activation

Upstream regulators (CollecTRI, top): AHR, AHRR, ARNT

miRNA regulators (miRDB)

97 targeting AHRR, 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-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6752-3P	99.72	66.71	1587

Literature-anchored findings (GeneRIF, showing 40)

• Pro185Ala polymorphism is weakly associated with micropenis. (PMID:11835227)
• None of the polymorphisms were found to play a key role in CYP1A1 inducibility or in the susceptibility to develop lung cancer (PMID:12777964)
• there existed characteristic differences in the basal levels of aryl hydrocarbon receptor repressor and cytochrome P450 1A1 expression in mononuclear cells, as well as in their inducibility among MNCs from various types of human bloods (PMID:14672759)
• Negative feedback effect of AHRR on dioxin-related signaling is weaker for proline allele than for alanine allele, and hypomorphic function of proline allele exerts recessive adverse effect on male fertility. (PMID:15474075)
• AHRR Pro185Ala polymorphism may constitute a susceptibility locus for the development of micropenis in response to dioxins. (PMID:15758562)
• AhRR codon 185 polymorphism is associated with susceptibility to and severity of endometriosis in Japanese women. (PMID:16084889)
• investigated which roles the AR polymorphisms as well as the R554K and P185A in the AHR and AHRR genes, respectively, may play in modifying the effect of exposure to organohalogen pollutants in regard to sperm Y : X ratio (PMID:17244640)
• the AhRR codon 185 and GSTT1 polymorphisms are associated with the risk of advanced stage endometriosis (PMID:17513317)
• AHRR Pro185Ala polymorphism contributed to a predisposition to male factor infertility in the Estonian population. A greater prevalence of the Ala/Ala genotype was found among infertile patients. (PMID:17559847)
• Suggest role for the AhRR in regulation of CYP1A1. (PMID:17890447)
• The NLS deletion mutant of GFP-AhRR was transported into the nuclear compartment in the presence of AhR nuclear translocator (Arnt). (PMID:17980155)
• These results therefore demonstrate that AHRR is a putative new tumor suppressor gene in multiple types of human cancers. (PMID:18172554)
• Data suggest that the aryl hydrocarbon receptor repressor might play a role of co-repressor on the transcriptional activity of the estrogen receptor alpha homodimer. (PMID:18565642)
• Using a panel of four genes (AHRR, p16INK4a, MT1G, and CLDN3) resulted in sensitivity and specificity of 50% and 68%, respectively and may have utility for early detection of esophageal squamous dysplasia and early ESCC. (PMID:19137073)
• The SUMOylation of both AhRR and Arnt is important for the efficient transcriptional repression activity of the AhRR/Arnt heterodimer (PMID:19251700)
• Results identify aryl hydrocarbon receptor (AHR) repressor (AHRR) Delta8 as the active form of human AHRR and reveal novel aspects of its function and specificity as a repressor of AHR. (PMID:19380484)
• AHHR genotyping may help to identify a subpopulation of women who are susceptible to the earlier onset of endometriosis. (PMID:19501819)
• In the single SNP analysis, GSTM1 null type and AhRR variant type were associated with a significantly increased risk of endometriosis. (PMID:22017422)
• AHRR methylation is associated with smoking. (PMID:22232023)
• a substantial subset of soft tissue angiofibroma is characterized by a t(5;8)(p15;q13), resulting in the expression of in-frame AHRR/NCOA2 and NCOA2/AHRR fusion transcripts. (PMID:22337624)
• These data clearly indicate that repressed CYP1 activity in primary human skin fibroblasts is not causally related to AhRR expression, which may serve a different, yet unknown, biological function. (PMID:22951721)
• in primary gastric adenocarcinoma, AHRR may play as a suppressor gene and its expression status has the potential to be an independent prognostic factor (PMID:22952704)
• methylation at AHRR (cg05575921) is associated with smoking status (PMID:23070629)
• Aryl hydrocarbon receptor repressor genotypes predict the inducibility of CYP1A2 in people highly exposed to toxic dioxin-like chemicals (PMID:23168330)
• TTP directly binds to the AHRR 3’UTR. TTP acts as a negative regulator of AHRR and may affect tumor development through induction of tumor suppressor genes. (PMID:23583445)
• a high frequency of the AhRR SNP can be a risk factor in the incidence of oral cancer and other neoplasias in Papua New Guinea due to higher inducibility of CYP1A2. (PMID:23648678)
• Selected genetic polymorphisms in the AHR-signaling pathway (i.e., AHRR) and CLOCK may play a role in decreasing the risk for experiencing insomnia during the menopausal transition. (PMID:23768840)
• The study expands the region of AHRR methylation altered in response to maternal smoking during pregnancy and reveals the tissue-specific nature of epigenetic responses to environmental exposures in utero. (PMID:24270552)
• Knockdown of TiPARP, but not AHRR, increased 2,3,7,8-tetrachlorodibenzo-p-dioxin - induced CYP1A1 mRNA and AHR protein levels. (PMID:24806346)
• In conclusion, offspring AHRR DNA methylation was associated with maternal obesity during pregnancy as well as infant gestational age and birth weight-for-gestational age. (PMID:26252179)
• AHRR methylation in monocytes may be a part of the biological link between cigarette smoking and atherosclerosis (PMID:26307030)
• Maternal-smoking sensitive CpG sites in newborns were significantly associated with cg05575921 SNP located proximal to AHRR. (PMID:27403598)
• In the AHRRNCOA2 protein, the Cterminal part of AHRR is replaced by the Cterminal part of NCOA2 which contains two activation domains (PMID:27633981)
• Study demonstrates that AHRR and F2RL3 methylation are strong predictors individually for lung cancer development. (PMID:27924164)
• In conclusion, we found that AHRR (cg05575921) hypomethylation was associated with smoking, high smoking-related morbidity and with high all-cause mortality. (PMID:28100713)
• This study demonstrated that the polymorphisms of aromatic hydrocarbon receptor repressor rs2292596 was significant with genetic susceptibility to rheumatoid arthritis patients; furthermore, it suggests the G allele of aromatic hydrocarbon receptor rs2292596 might be associated with a dangerous effect on rheumatoid arthritis in Han Chinese populations. (PMID:28403070)
• We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of Nonsyndromic cleft lip with or without cleft palate (NSCL/P) . Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P (PMID:28425186)
• DNA methylation at AHRR is associated with smoking. (PMID:28436623)
• Prospective study demonstrated that AHRR and F2RL3 methylation levels had inverse relationships with self-reported smoking status and accurately discriminated for both current- and former- smoking. Moreover, methylation markers distinguished former smokers from never-smokers with high accuracy and significantly associated with an increased risk of lung cancer. (PMID:28453567)
• AHRR DNA methylation of cord and maternal blood might be independently associated with full term, low birth weight infants in different ways. (PMID:28454697)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ahrrb	ENSDARG00000052618
danio_rerio	ahrra	ENSDARG00000099702
mus_musculus	Ahrr	ENSMUSG00000021575
drosophila_melanogaster	ss	FBGN0003513
caenorhabditis_elegans	ahr-1	WBGENE00000096

Paralogs (1): AHR (ENSG00000106546)

Protein

Protein identifiers

Aryl hydrocarbon receptor repressor — A9YTQ3 (reviewed: A9YTQ3)

Alternative names: Class E basic helix-loop-helix protein 77

All UniProt accessions (8): A0A494BZY4, A0A7I2PK40, D6RE68, E5RFG4, E5RGQ2, E5RHE0, G3V143, H0YA43

UniProt curated annotations — full annotation on UniProt →

Function. Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation. Represses the transcription activity of AHR by competing with AHR for heterodimer formation with ARNT and subsequently binding to the xenobiotic response element (XRE) sequence present in the promoter regulatory region of a variety of genes. Represses CYP1A1 by binding the XRE sequence and recruiting ANKRA2, HDAC4 and/or HDAC5. Autoregulates its expression by associating with its own XRE site. Represses AHR transcription activity. Also represses transcription mediated by HIF1A and EPAS1/HIF2A but does not repress NR1I2/PXR or ESR1 transcriptional activities. Does not repress AHR transcription activity.

Subunit / interactions. Heterodimer with ARNT; formation of the heterodimer results in repression of the transcription activity of AHR. Interacts with ANKRA2, HDAC4 and HDAC5. Interacts with ARNT. Does not interact with ARNT.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in testis, lung, ovary, spleen and pancreas. Highly expressed in mononuclear cells (MNCs) from umbilical cord blood. Down-regulated in malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary. Predominant form which is widely expressed in multiple adult and fetal tissues. Minor form which is expressed at low levels.

Induction. By 3-methylcholanthrene (3-MC) in MNCs from adults. By the heterodimer AHR/ARNT.

Polymorphism. The Ala-189 allele may be a susceptibility factor for dioxin-related male infertility. Homozygosity for Ala-189 is observed in azoospermic individuals at higher frequency than in normozoospermic individuals. Might also be associated with susceptibility to and severity of endometriosis.

Isoforms (2)

UniProt ID	Names	Canonical?
A9YTQ3-1	1, AHRRdelta8	yes
A9YTQ3-3	2, AHRR715

RefSeq proteins (2): NP_001364165, NP_001364168 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR039091	AHR/AHRR	Family
IPR039092	AHRR_bHLH	Domain

Pfam: PF00010, PF00989

UniProt features (36 total): helix 11, strand 7, region of interest 6, sequence variant 4, domain 2, compositionally biased region 2, cross-link 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5Y7Y	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A9YTQ3-F1	53.28	0.20

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 (2): 573, 656

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-211976	Endogenous sterols
R-HSA-211981	Xenobiotics
R-HSA-8937144	Aryl hydrocarbon receptor signalling

MSigDB gene sets: 119 (showing top): GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, WEI_MYCN_TARGETS_WITH_E_BOX, WANG_LMO4_TARGETS_DN, NIKOLSKY_BREAST_CANCER_5P15_AMPLICON, GOBP_INTRACELLULAR_RECEPTOR_SIGNALING_PATHWAY, GOCC_RECEPTOR_COMPLEX, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, NIKOLSKY_MUTATED_AND_AMPLIFIED_IN_BREAST_CANCER, FALVELLA_SMOKERS_WITH_LUNG_CANCER, GSE13762_CTRL_VS_125_VITAMIND_DAY12_DC_UP, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MIKKELSEN_IPS_HCP_WITH_H3_UNMETHYLATED, WONG_ADULT_TISSUE_STEM_MODULE, MIKKELSEN_ES_HCP_WITH_H3_UNMETHYLATED

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), xenobiotic metabolic process (GO:0006805), regulation of DNA-templated transcription (GO:0006355), response to xenobiotic stimulus (GO:0009410)

GO Molecular Function (5): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), nuclear receptor activity (GO:0004879), protein dimerization activity (GO:0046983), DNA binding (GO:0003677)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), aryl hydrocarbon receptor complex (GO:0034751), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	2
Regulation of lipid metabolism by PPARalpha	1
Biological oxidations	1
Phase I - Functionalization of compounds	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
metabolic process	1
cellular response to xenobiotic stimulus	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
response to chemical	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
protein binding	1
nucleic acid binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
signaling receptor complex	1
intracellular protein-containing complex	1
cytoplasm	1

Protein interactions and networks

STRING

652 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AHRR	CYP1A1	P04798	892
AHRR	CYP1B1	Q16678	746
AHRR	F2RL3	Q96RI0	717
AHRR	LMBR1L	Q6UX01	674
AHRR	ANKRA2	Q9H9E1	632
AHRR	AIP	O00170	602
AHRR	MYO1G	B0I1T2	596
AHRR	TIPARP	Q7Z3E1	572
AHRR	CYP1A2	P05177	559
AHRR	ESR1	P03372	495
AHRR	GPR15	P49685	480
AHRR	NRIP1	P48552	453
AHRR	KLF6	Q99612	446
AHRR	GFI1	Q99684	433
AHRR	PPIG	Q13427	424

IntAct

1 interactions, top by confidence:

A	B	Type	Score
	AHRR	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): ARNT (Co-crystal Structure), ARNT (Reconstituted Complex), AHRR (Affinity Capture-RNA), AHRR (Affinity Capture-Western), AHRR (Two-hybrid), AHRR (Affinity Capture-RNA), AHRR (Affinity Capture-RNA), ESR1 (Affinity Capture-Western), HDAC4 (Affinity Capture-Western), HDAC5 (Affinity Capture-Western), ANKRA2 (Affinity Capture-Western)

ESM2 similar proteins: A1YGK1, A2T7E6, A4D1S0, A9YTQ3, B1WBS3, I7HJS4, O43593, O43918, O60304, O75593, O95201, P0C6A0, P0C7X2, P97609, Q2MHN3, Q3B7M4, Q3SY56, Q3U133, Q58DK7, Q5JPB2, Q5SXI5, Q5T619, Q61645, Q6KAU7, Q6NUN9, Q6ZMS7, Q76NI1, Q7Z6P3, Q8BZ34, Q8BZW2, Q8CGW9, Q8IWN7, Q8IXT2, Q8IZ20, Q8NBB4, Q8NDX1, Q8NHY3, Q91X45, Q96PX9, Q99558

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, E7FFX1, O02747, O44712, O57539, O61734, P30561, P35869, P41738, P70365

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	0
Uncertain significance	152
Likely benign	21
Benign	6

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1180547	GRCh37/hg19 5p15.33(chr5:13200-4012072)x1	Pathogenic
147750	GRCh38/hg38 5p15.33(chr5:22149-1429599)x1	Pathogenic
152721	GRCh38/hg38 5p15.33-15.32(chr5:22149-4833626)x1	Pathogenic
154579	GRCh38/hg38 5p15.33(chr5:22149-1659135)x3	Pathogenic
154951	GRCh38/hg38 5p15.33-15.32(chr5:22149-5059896)x1	Pathogenic
155265	GRCh38/hg38 5p15.33-15.32(chr5:22149-5102586)x1	Pathogenic
1711872	GRCh37/hg19 5p15.33(chr5:113576-2027194)x1	Pathogenic
3062835	GRCh37/hg19 5p15.33(chr5:113576-3612214)x1	Pathogenic
395562	GRCh37/hg19 5p15.33(chr5:22149-2965987)x1	Pathogenic
441756	GRCh37/hg19 5p15.33(chr5:113576-4175855)x1	Pathogenic
563021	GRCh37/hg19 5p15.33(chr5:113576-1816055)x1	Pathogenic
563022	GRCh37/hg19 5p15.33-15.32(chr5:113576-5884399)x1	Pathogenic
57057	GRCh38/hg38 5p15.33(chr5:22149-1826256)x1	Pathogenic
59554	GRCh38/hg38 5p15.33-15.31(chr5:22149-7213275)x1	Pathogenic
59557	GRCh38/hg38 5p15.33(chr5:22149-3556942)x1	Pathogenic
59578	GRCh38/hg38 5p15.33(chr5:37694-2913205)x1	Pathogenic
814651	GRCh37/hg19 5p15.33(chr5:113576-4325585)x1	Pathogenic
831918	NC_000005.10:g.(?218349)(1297373_?)del	Pathogenic
979670	GRCh37/hg19 5p15.33(chr5:113576-4305172)x1	Pathogenic

SpliceAI

3818 predictions. Top by Δscore:

Variant	Effect	Δscore
5:353728:A:AG	acceptor_gain	1.0000
5:353729:G:GG	acceptor_gain	1.0000
5:353729:GGA:G	acceptor_gain	1.0000
5:353907:CCAAG:C	donor_loss	1.0000
5:353908:CAAGG:C	donor_loss	1.0000
5:353909:AAG:A	donor_loss	1.0000
5:353910:AGG:A	donor_loss	1.0000
5:353912:GTA:G	donor_loss	1.0000
5:353913:T:G	donor_loss	1.0000
5:376608:A:AG	acceptor_gain	1.0000
5:376609:G:GA	acceptor_gain	1.0000
5:376609:GTC:G	acceptor_gain	1.0000
5:413342:A:AG	acceptor_gain	1.0000
5:413343:G:GA	acceptor_gain	1.0000
5:413343:GT:G	acceptor_gain	1.0000
5:413343:GTCT:G	acceptor_gain	1.0000
5:413343:GTCTC:G	acceptor_gain	1.0000
5:422727:A:AG	acceptor_gain	1.0000
5:422727:AGAC:A	acceptor_gain	1.0000
5:422727:AGACG:A	acceptor_gain	1.0000
5:422728:G:GG	acceptor_gain	1.0000
5:422728:GACG:G	acceptor_gain	1.0000
5:422728:GACGG:G	acceptor_gain	1.0000
5:423810:C:A	acceptor_gain	1.0000
5:423831:T:TA	acceptor_gain	1.0000
5:432462:GA:G	acceptor_gain	1.0000
5:343887:TTCCA:T	acceptor_loss	0.9900
5:343888:TCCA:T	acceptor_loss	0.9900
5:343890:CA:C	acceptor_loss	0.9900
5:343891:A:C	acceptor_loss	0.9900

AlphaMissense

4510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:353852:A:T	D66V	0.999
5:413356:T:C	F126L	0.999
5:413358:T:A	F126L	0.999
5:413358:T:G	F126L	0.999
5:413425:T:C	F149L	0.999
5:413426:T:C	F149S	0.999
5:413427:C:A	F149L	0.999
5:413427:C:G	F149L	0.999
5:423972:T:C	F239L	0.999
5:423974:C:A	F239L	0.999
5:423974:C:G	F239L	0.999
5:353769:G:C	K38N	0.998
5:353769:G:T	K38N	0.998
5:353773:C:G	H40D	0.998
5:353786:T:A	L44H	0.998
5:353852:A:C	D66A	0.998
5:353854:A:G	K67E	0.998
5:353856:G:C	K67N	0.998
5:353856:G:T	K67N	0.998
5:353867:T:C	L71P	0.998
5:353873:T:C	L73P	0.998
5:353875:A:C	S74R	0.998
5:353877:T:A	S74R	0.998
5:353877:T:G	S74R	0.998
5:413357:T:C	F126S	0.998
5:413387:T:A	I136K	0.998
5:422787:T:C	F171S	0.998
5:427817:T:C	F244S	0.998
5:427822:G:A	G246R	0.998
5:427822:G:C	G246R	0.998

dbSNP variants (sampled 300 via entrez): RS1000000532 (5:338272 C>T), RS1000017652 (5:413505 C>A,G,T), RS1000050341 (5:331416 T>A), RS1000091569 (5:337993 C>T), RS1000152854 (5:417354 G>A), RS1000158068 (5:380783 A>C), RS1000165264 (5:344371 T>C), RS1000181466 (5:376769 C>T), RS1000183999 (5:403136 T>C), RS1000198928 (5:352826 C>T), RS1000241553 (5:359528 G>A,C), RS1000244280 (5:393496 C>G,T), RS1000264377 (5:351854 CAG>C), RS1000271495 (5:345640 A>G), RS1000283013 (5:435316 C>G,T)

Disease associations

OMIM: gene MIM:606517 | disease phenotypes: MIM:613989, MIM:178500

GenCC curated gene-disease

Mondo (3): prostate cancer (MONDO:0008315), dyskeratosis congenita, autosomal dominant 2 (MONDO:0013521), interstitial lung disease 2 (MONDO:0800497)

Orphanet (3): Familial prostate cancer (Orphanet:1331), Idiopathic pulmonary fibrosis (Orphanet:2032), Acute interstitial pneumonia (Orphanet:79126)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001077_5	Cystic fibrosis severity	4.000000e-06
GCST001343_15	Fat distribution (HIV)	7.000000e-06
GCST004988_437	Breast cancer	4.000000e-09
GCST005580_317	Intraocular pressure	6.000000e-09
GCST006628_50	Systolic blood pressure	8.000000e-10
GCST007876_18	Estimated glomerular filtration rate	4.000000e-10
GCST010083_227	Hemoglobin levels	6.000000e-12
GCST012227_1334	Hip circumference adjusted for BMI	5.000000e-09
GCST90020028_1027	Hip circumference adjusted for BMI	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004695	intraocular pressure measurement
EFO:0006335	systolic blood pressure
EFO:0004509	hemoglobin measurement
EFO:0008039	BMI-adjusted hip circumference

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: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2292596	Efficacy	3	methotrexate	Rheumatoid arthritis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2292596	AHRR	3	0.00	1	methotrexate

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases reaction, increases expression, increases activity, increases reaction, affects expression (+2 more)	24
Benzo(a)pyrene	decreases reaction, increases activity, affects expression, affects methylation, decreases expression (+1 more)	13
Tobacco Smoke Pollution	decreases methylation, increases expression, affects methylation	7
Particulate Matter	decreases methylation, increases abundance, increases expression	4
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	3
2,3,4,7,8-pentachlorodibenzofuran	increases expression	3
1,2,3,7,8-pentachlorodibenzo-p-dioxin	increases expression	3
Dioxins	increases response to substance	3
Polycyclic Aromatic Hydrocarbons	affects reaction, decreases expression, increases expression, affects expression	3
fluoranthene	affects reaction, decreases expression, affects cotreatment	2
pyrene	affects reaction, decreases expression, affects cotreatment	2
phenanthrene	affects cotreatment, affects reaction, decreases expression	2
naphthalene	affects cotreatment, affects reaction, decreases expression	2
anthracene	affects cotreatment, affects reaction, decreases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	2
Cadmium	affects methylation, increases abundance, increases expression	2
Methylcholanthrene	increases expression	2
Quercetin	decreases expression, decreases reaction, increases expression	2
Smoke	affects reaction, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
PF-06840003	decreases reaction, increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
terbufos	increases methylation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects response to substance	1
2,3,7,8-tetrachlorodibenzofuran	increases expression	1
beta-lapachone	decreases expression	1

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