RNF40

Summary

RNF40 (ring finger protein 40, HGNC:16867) is a protein-coding gene on chromosome 16p11.2, encoding E3 ubiquitin-protein ligase BRE1B (O75150). Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of ‘Lys-120’ of histone H2B (H2BK120ub1). It is a selective cancer dependency (DepMap: 46.6% of cell lines).

The protein encoded by this gene contains a RING finger, a motif known to be involved in protein-protein and protein-DNA interactions. This protein was reported to interact with the tumor suppressor protein RB1. Studies of the rat counterpart suggested that this protein may function as an E3 ubiquitin-protein ligase, and facilitate the ubiquitination and degradation of syntaxin 1, which is an essential component of the neurotransmitter release machinery. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9810 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 134 total
• Cancer dependency (DepMap): dependent in 46.6% of screened cell lines
• MANE Select transcript: NM_014771

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16867
Approved symbol	RNF40
Name	ring finger protein 40
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0661, RBP95, BRE1B, STARING
Ensembl gene	ENSG00000103549
Ensembl biotype	protein_coding
OMIM	607700
Entrez	9810

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000324685, ENST00000357890, ENST00000493683, ENST00000563683, ENST00000563909, ENST00000564260, ENST00000565931, ENST00000565995, ENST00000566703, ENST00000566811, ENST00000567365, ENST00000602784, ENST00000864896, ENST00000864897, ENST00000864898, ENST00000864899, ENST00000928405, ENST00000928406, ENST00000928407, ENST00000928408, ENST00000946788, ENST00000946789, ENST00000946790, ENST00000946791

RefSeq mRNA: 4 — MANE Select: NM_014771 NM_001207033, NM_001207034, NM_001286572, NM_014771

CCDS: CCDS10691, CCDS55994

Canonical transcript exons

ENST00000324685 — 20 exons

Exon	Start	End
ENSE00001380635	30769186	30769398
ENSE00002313340	30762322	30762360
ENSE00003489974	30765181	30765327
ENSE00003503053	30771833	30771973
ENSE00003503728	30764179	30764385
ENSE00003510357	30763118	30763285
ENSE00003513884	30764938	30765059
ENSE00003533282	30763418	30763559
ENSE00003571828	30768103	30768530
ENSE00003582806	30767894	30768015
ENSE00003583829	30773938	30776307
ENSE00003594140	30768838	30768987
ENSE00003596977	30766163	30766282
ENSE00003604776	30762475	30762677
ENSE00003633370	30772089	30772190
ENSE00003638891	30765425	30765499
ENSE00003661844	30768619	30768736
ENSE00003679220	30766379	30766558
ENSE00003689673	30766741	30766876
ENSE00003753804	30769475	30769600

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 96.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5260 / max 256.7162, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153729	29.4606	1821
153728	5.0967	1739
153726	0.4898	289
153727	0.4789	230

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	96.76	gold quality
cortical plate	UBERON:0005343	96.46	gold quality
left testis	UBERON:0004533	96.25	gold quality
right testis	UBERON:0004534	96.14	gold quality
ganglionic eminence	UBERON:0004023	96.11	gold quality
mucosa of transverse colon	UBERON:0004991	95.04	gold quality
adrenal tissue	UBERON:0018303	94.94	gold quality
islet of Langerhans	UBERON:0000006	94.60	gold quality
right lobe of thyroid gland	UBERON:0001119	94.47	gold quality
granulocyte	CL:0000094	94.45	gold quality
sural nerve	UBERON:0015488	94.28	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.20	gold quality
right adrenal gland	UBERON:0001233	94.15	gold quality
right adrenal gland cortex	UBERON:0035827	94.15	gold quality
skin of leg	UBERON:0001511	94.14	gold quality
left lobe of thyroid gland	UBERON:0001120	94.09	gold quality
lower esophagus mucosa	UBERON:0035834	94.05	gold quality
cerebellar hemisphere	UBERON:0002245	94.04	gold quality
left uterine tube	UBERON:0001303	94.03	gold quality
right ovary	UBERON:0002118	94.02	gold quality
cerebellar cortex	UBERON:0002129	93.93	gold quality
monocyte	CL:0000576	93.90	gold quality
endocervix	UBERON:0000458	93.87	gold quality
adenohypophysis	UBERON:0002196	93.87	gold quality
testis	UBERON:0000473	93.82	gold quality
leukocyte	CL:0000738	93.78	gold quality
ectocervix	UBERON:0012249	93.77	gold quality
left adrenal gland	UBERON:0001234	93.73	gold quality
right frontal lobe	UBERON:0002810	93.71	gold quality
left adrenal gland cortex	UBERON:0035825	93.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

47 targeting RNF40, 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-6748-5P	100.00	65.81	1057
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-1322	97.98	68.96	625
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-517-5P	97.13	68.43	781

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 46.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• Functional Analysis of the rat counterpart (PMID:12121982)
• Formation of trimeric complex UbcH6 and RNF20/40 with PAF stimulates histone 2B monoubiquitination activity in vitro (PMID:16307923)
• the observed defects in the radiation response of Bre1a/b-deficient cells (PMID:20738173)
• Studies indicate that H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. (PMID:21827756)
• RNF40 cooperates with SUPT16H to induce dynamic changes in chromatin structure during DNA double-strand break repair. (PMID:22031019)
• our results suggest that RNF20 and RNF40, either via ubiquitylation of H2B or other targets, are coupled to the proliferation of prostate cancer cells. (PMID:22155569)
• We show that Bre1 (human BRE1A/B (RNF20/40) and mouse Bre1a/b (Rnf20/40)) acts as an important suppressor of chromosomal instability (PMID:22354749)
• the RNF20/40 complex, a major ubiquitin ligase catalysing histone H2B monoubiquitination, interacts with the motor protein Eg5 during mitosis and participates in spindle assembly. (PMID:27557628)
• The authors also show that the RING domains of RNF20 and RNF40 can form a stable heterodimer that is active. (PMID:27569044)
• Manipulation of key H2Bub1 E3 ubiquitin ligases, RNF20, RNF40 and BRCA1, in ovarian cancer cell line models modulated H2Bub1 levels, indicative of the role of these RING finger ligases in monoubiquitination of H2Bub1 in vitro (PMID:27798111)
• Our findings suggest that RNF40 plays a central role in the maintenance of tumorigenic features and inflammatory signaling by promoting nuclear NF-kappaB activity. (PMID:30321325)
• Cooperative physical interactions among eEF1BdeltaL, RNF20/40, and HSF1 synergistically promote expression of heat shock-responsive genes. In addition, eEF1BdeltaL is a novel ubiquitylation target of RNF20/40 and elucidating its function. This provides a molecular mechanism for the cooperative function of distinct transcription factors in heat shock-responsive gene transcription. (PMID:30649429)
• The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing. (PMID:31152661)
• Findings reveal that RNF40 is essential for maintaining tumorigenic features of colorectal cancer cells in vitro by controlling the expression of genes encoding central apoptotic regulators. (PMID:31266541)
• The H2B ubiquitin-protein ligase RNF40 is required for somatic cell reprogramming. (PMID:32341358)
• The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis. (PMID:33070155)
• Epigenetic modification and a role for the E3 ligase RNF40 in cancer development and metastasis. (PMID:33199825)
• RNF40 epigenetically modulates glycolysis to support the aggressiveness of basal-like breast cancer. (PMID:37770435)
• Hypoxia-inducible factor 1 recruits FACT and RNF20/40 to mediate histone ubiquitination and transcriptional activation of target genes. (PMID:38517892)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf40	ENSDARG00000054201
mus_musculus	Rnf40	ENSMUSG00000030816
rattus_norvegicus	Rnf40	ENSRNOG00000018840
drosophila_melanogaster	Bre1	FBGN0086694
caenorhabditis_elegans		WBGENE00007008

Paralogs (1): RNF20 (ENSG00000155827)

Protein

Protein identifiers

E3 ubiquitin-protein ligase BRE1B — O75150 (reviewed: O75150)

Alternative names: 95 kDa retinoblastoma-associated protein, RING finger protein 40, RING-type E3 ubiquitin transferase BRE1B

All UniProt accessions (9): O75150, A0A087WTK2, A8K6K1, H3BP71, H3BQ99, H3BS50, H3BUL6, I3L332, R4GN66

UniProt curated annotations — full annotation on UniProt →

Function. Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of ‘Lys-120’ of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 ‘Lys-4’ and ‘Lys-79’ methylation (H3K4me and H3K79me, respectively). It thereby plays a central role in histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes. (Microbial infection) Promotes the human herpesvirus 8 (KSHV) lytic cycle by inducing the expression of lytic viral genes including the latency switch gene RTA/ORF50.

Subunit / interactions. Component of the RNF20/40 complex (also known as BRE1 complex) probably composed of 2 copies of RNF20/BRE1A and 2 copies of RNF40/BRE1B. Interacts with UBE2E1/UBCH6. Interacts with RB1 and WAC. (Microbial infection) Interacts with human herpesvirus 8 (KSHV) protein RTA/ORF50; this interaction targets the SMC5-SMC6 complex for proteasomal degradation.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed. Expressed at higher level in testis, heart and pancreas, while it is only weakly expressed in lung, skeletal muscle and small intestine.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the BRE1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75150-1	1	yes
O75150-3	3
O75150-4	4

RefSeq proteins (4): NP_001193962, NP_001193963, NP_001273501, NP_055586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013956	E3_ubiquit_lig_Bre1	Family
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR058642	BRE1A/B-like_dom	Domain
IPR058643	BRE1-like_CC	Domain

Pfam: PF00097, PF26052, PF26095

UniProt features (46 total): sequence conflict 8, modified residue 6, compositionally biased region 4, strand 4, coiled-coil region 4, region of interest 3, splice variant 3, mutagenesis site 3, turn 3, cross-link 2, sequence variant 2, helix 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8GUJ	ELECTRON MICROSCOPY	2.8
8GUI	ELECTRON MICROSCOPY	2.81
8IEJ	ELECTRON MICROSCOPY	3.12
9KQO	ELECTRON MICROSCOPY	3.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75150-F1	73.70	0.24

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 (8): 20, 42, 355, 517, 528, 585, 578, 579

Mutagenesis-validated functional residues (3):

Position	Phenotype
109	abolishes interaction with rb1.
111	abolishes interaction with rb1.
113	abolishes interaction with rb1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-8852135	Protein ubiquitination

MSigDB gene sets: 101 (showing top): SP3_Q3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, BROWNE_HCMV_INFECTION_16HR_UP, SCIBETTA_KDM5B_TARGETS_UP, BROWNE_HCMV_INFECTION_12HR_UP, AML_Q6, chr16p11, GOBP_REGULATION_OF_CELL_CYCLE, TCCCCAC_MIR491, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_MITOTIC_CELL_CYCLE, RYTTCCTG_ETS2_B, RFX1_02, CTCAAGA_MIR526B

GO Biological Process (4): chromatin organization (GO:0006325), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (9): mRNA 3’-UTR binding (GO:0003730), zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), HULC complex (GO:0033503)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Protein ubiquitination	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular component organization	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
mRNA binding	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
identical protein binding	1
protein dimerization activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
ubiquitin ligase complex	1
chromatin	1
ubiquitin conjugating enzyme complex	1

Protein interactions and networks

STRING

2414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF40	RNF20	Q5VTR2	983
RNF40	H2BC21	Q16778	842
RNF40	DDB1	Q16531	837
RNF40	CDC73	Q6P1J9	824
RNF40	UBE2A	P49459	819
RNF40	PAF1	Q8N7H5	790
RNF40	H2BC17	P23527	777
RNF40	UBE2B	P23567	773
RNF40	H2BC1	Q96A08	772
RNF40	H2BK1	A0A2R8Y619	772
RNF40	H2BC12	O60814	772
RNF40	H2BC11	P06899	772
RNF40	H2BW2	P0C1H6	772
RNF40	H2BC3	P33778	772
RNF40	H2BC12L	P57053	772
RNF40	H2BC18	Q5QNW6	772
RNF40	H2BW1	Q7Z2G1	772
RNF40	H2BC26	Q8N257	772
RNF40	H2BC9	Q93079	772
RNF40	H2BC15	Q99877	772
RNF40	H2BC14	Q99879	772

IntAct

187 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
RNF20	RNF40	psi-mi:“MI:0915”(physical association)	0.820
RNF40	RNF20	psi-mi:“MI:0915”(physical association)	0.820
RNF20	RNF40	psi-mi:“MI:0220”(ubiquitination reaction)	0.820
RNF40	RNF20	psi-mi:“MI:0914”(association)	0.820
PRPF19	PLRG1	psi-mi:“MI:0914”(association)	0.770
RNF40	NCBP1	psi-mi:“MI:0915”(physical association)	0.740
MED4	MED14	psi-mi:“MI:0914”(association)	0.740
SNX32	SNX2	psi-mi:“MI:0914”(association)	0.740
NCBP1	RNF40	psi-mi:“MI:0915”(physical association)	0.740
UBE2I	RNF40	psi-mi:“MI:0915”(physical association)	0.720
RNF40	UBE2I	psi-mi:“MI:0915”(physical association)	0.720
RNF40	SFR1	psi-mi:“MI:0915”(physical association)	0.670
SFR1	RNF40	psi-mi:“MI:0915”(physical association)	0.670
RNF40	HTT	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (400): RNF40 (Affinity Capture-Western), UBE2A (Reconstituted Complex), UBE2B (Reconstituted Complex), RNF40 (Two-hybrid), RNF40 (Two-hybrid), AMOTL2 (Two-hybrid), CCDC146 (Two-hybrid), SFR1 (Two-hybrid), RNF40 (Affinity Capture-RNA), RNF40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS), RNF40 (Affinity Capture-MS)

ESM2 similar proteins: A0PJP4, A0PJT0, A2VDP1, D3ZUQ0, O60271, O75150, P46825, Q0IHE5, Q0P485, Q0V989, Q14BN4, Q17QG3, Q28623, Q2QLI6, Q3U319, Q4R7K7, Q4V872, Q58A65, Q5DTM8, Q5EBL4, Q5R5R4, Q5RAU7, Q5VTR2, Q5ZLS3, Q653N3, Q68CZ1, Q6DFC2, Q6GQ73, Q6IMY1, Q7Z3E2, Q86VS8, Q8BR07, Q8BUK6, Q8C9S4, Q8CG73, Q8CJB9, Q8IYE1, Q8L7S4, Q8R4C2, Q8TD16

Diamond homologs: A2VDP1, A2XW69, O74563, O75150, P34537, Q09463, Q3U319, Q4P3X7, Q4R7K7, Q5DTM8, Q5RAU7, Q5VTR2, Q5ZLS3, Q60YN5, Q6LFN2, Q7XU27, Q8CJB9, Q9R1A8, Q9VRP9, A2ZAC2, O64425, O88846, P0CQ62, P0CQ63, P78317, Q2U9B0, Q336R3, Q4WDD7, Q568Y3, Q5RFK9, Q5ZIR9, Q6CHI1, Q6PC78, Q7S304, Q8GUK7, Q8RXD6, Q91YT2, Q96GF1, Q99942, Q9C895

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATM	up-regulates	RNF40	phosphorylation
Ub:E2	“up-regulates activity”	RNF40	ubiquitination
ATM	“up-regulates activity”	RNF40	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 168 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
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	6	12.2×	2e-03
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	6	11.2×	2e-03
Respiratory Syncytial Virus Infection Pathway	6	11.2×	2e-03
Adipogenesis	7	10.3×	2e-03
Regulation of lipid metabolism by PPARalpha	7	9.3×	2e-03
Formation of RNA Pol II elongation complex	5	9.1×	6e-03
RNA Polymerase II Transcription Elongation	5	9.1×	6e-03
E3 ubiquitin ligases ubiquitinate target proteins	5	9.1×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	7	14.5×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2623 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30762220:A:G	donor_gain	1.0000
16:30762225:G:GT	donor_gain	1.0000
16:30762473:A:AG	acceptor_gain	1.0000
16:30762474:G:GG	acceptor_gain	1.0000
16:30762609:C:G	donor_gain	1.0000
16:30762661:G:GT	donor_gain	1.0000
16:30763112:T:TA	acceptor_gain	1.0000
16:30763113:G:A	acceptor_gain	1.0000
16:30763113:GGTA:G	acceptor_loss	1.0000
16:30763115:TA:T	acceptor_loss	1.0000
16:30763116:A:AC	acceptor_loss	1.0000
16:30763116:A:AG	acceptor_gain	1.0000
16:30763116:AGGAG:A	acceptor_gain	1.0000
16:30763117:G:GA	acceptor_gain	1.0000
16:30763117:GGAGG:G	acceptor_gain	1.0000
16:30763281:CCCAG:C	donor_loss	1.0000
16:30763282:CCAG:C	donor_loss	1.0000
16:30763283:CAGG:C	donor_loss	1.0000
16:30763284:AGG:A	donor_loss	1.0000
16:30763285:GGT:G	donor_loss	1.0000
16:30763286:G:GA	donor_loss	1.0000
16:30763287:T:G	donor_loss	1.0000
16:30763412:TTCCA:T	acceptor_loss	1.0000
16:30763413:TCCA:T	acceptor_loss	1.0000
16:30763414:CCA:C	acceptor_loss	1.0000
16:30763415:CA:C	acceptor_loss	1.0000
16:30763416:A:AG	acceptor_gain	1.0000
16:30763416:AGCT:A	acceptor_gain	1.0000
16:30763416:AGCTG:A	acceptor_gain	1.0000
16:30763417:G:GT	acceptor_gain	1.0000

AlphaMissense

6475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:30765296:T:C	L296P	1.000
16:30765308:T:C	L300P	1.000
16:30766448:T:C	F395L	1.000
16:30766450:C:A	F395L	1.000
16:30766450:C:G	F395L	1.000
16:30766832:T:C	L462P	1.000
16:30766835:G:C	R463P	1.000
16:30766843:T:C	F466L	1.000
16:30766845:T:A	F466L	1.000
16:30766845:T:G	F466L	1.000
16:30766850:A:C	Q468P	1.000
16:30766856:T:C	L470P	1.000
16:30766861:G:C	A472P	1.000
16:30767900:T:A	I479N	1.000
16:30767912:T:C	M483T	1.000
16:30767912:T:G	M483R	1.000
16:30767921:T:C	L486P	1.000
16:30767929:A:C	S489R	1.000
16:30767931:T:A	S489R	1.000
16:30767931:T:G	S489R	1.000
16:30767933:T:C	L490P	1.000
16:30767954:T:C	L497P	1.000
16:30768651:T:C	L671P	1.000
16:30768654:T:C	L672P	1.000
16:30768657:T:C	L673P	1.000
16:30768665:T:G	Y676D	1.000
16:30768705:T:C	L689P	1.000
16:30768959:T:C	L740P	1.000
16:30769199:T:C	L754P	1.000
16:30769202:T:C	L755P	1.000

dbSNP variants (sampled 300 via entrez): RS1000129251 (16:30776332 A>AC), RS1000316597 (16:30773651 A>G), RS1000334876 (16:30770746 C>G), RS1000363318 (16:30767666 C>T), RS1000479164 (16:30767828 A>C,G,T), RS1000558135 (16:30761969 G>C), RS1000992488 (16:30762209 A>C,G,T), RS1001075788 (16:30761500 C>G,T), RS1001191906 (16:30760863 A>C,G), RS1001202986 (16:30770775 G>A,C), RS1001588448 (16:30768080 C>A), RS1002247475 (16:30761764 T>C,G), RS1002601654 (16:30762019 T>C), RS1002696455 (16:30766971 CCTT>C), RS1002750309 (16:30767251 C>T)

Disease associations

OMIM: gene MIM:607700 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004028_8	Immunoglobulin light chain (AL) amyloidosis	4.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, increases expression	3
Valproic Acid	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tetrabromobisphenol A	increases expression	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	decreases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Rotenone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE