EIF4ENIF1

Summary

EIF4ENIF1 (eukaryotic translation initiation factor 4E nuclear import factor 1, HGNC:16687) is a protein-coding gene on chromosome 22q12.2, encoding Eukaryotic translation initiation factor 4E transporter (Q9NRA8). EIF4E-binding protein that regulates translation and stability of mRNAs in processing bodies (P-bodies).

The protein encoded by this gene is a nucleocytoplasmic shuttle protein for the translation initiation factor eIF4E. This shuttle protein interacts with the importin alpha-beta complex to mediate nuclear import of eIF4E. It is predominantly cytoplasmic; its own nuclear import is regulated by a nuclear localization signal and nuclear export signals. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 56478 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ovarian failure (Moderate, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 165 total
• MANE Select transcript: NM_019843

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16687
Approved symbol	EIF4ENIF1
Name	eukaryotic translation initiation factor 4E nuclear import factor 1
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	4E-T, FLJ21601, Clast4, 2610509L04Rik
Ensembl gene	ENSG00000184708
Ensembl biotype	protein_coding
OMIM	607445
Entrez	56478

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 30 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000330125, ENST00000344710, ENST00000397518, ENST00000397520, ENST00000397523, ENST00000397525, ENST00000418321, ENST00000423097, ENST00000441289, ENST00000445424, ENST00000475437, ENST00000487671, ENST00000495101, ENST00000892291, ENST00000892292, ENST00000892293, ENST00000892294, ENST00000892295, ENST00000892296, ENST00000892297, ENST00000892298, ENST00000892299, ENST00000892300, ENST00000892301, ENST00000892302, ENST00000927345, ENST00000927346, ENST00000927347, ENST00000927348, ENST00000927349, ENST00000972526, ENST00000972527, ENST00000972528, ENST00000972529, ENST00000972530

RefSeq mRNA: 3 — MANE Select: NM_019843 NM_001164501, NM_001164502, NM_019843

CCDS: CCDS13898, CCDS54520

Canonical transcript exons

ENST00000330125 — 19 exons

Exon	Start	End
ENSE00001294653	31455136	31455315
ENSE00001300583	31450289	31450360
ENSE00001319440	31454144	31454376
ENSE00001320157	31488623	31488745
ENSE00001322202	31447426	31447565
ENSE00001325200	31471844	31471917
ENSE00001529053	31439367	31440121
ENSE00001599893	31458475	31458650
ENSE00001604706	31462932	31463133
ENSE00001720761	31489694	31489842
ENSE00001738983	31463681	31463967
ENSE00001745228	31455852	31455987
ENSE00002026736	31468175	31468302
ENSE00003483741	31448153	31448232
ENSE00003486270	31449348	31449531
ENSE00003547661	31440704	31440868
ENSE00003580280	31444606	31444690
ENSE00003617326	31442962	31443094
ENSE00003626640	31441774	31442118

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 97.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3297 / max 76.2334, expressed in 1763 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193710	6.3985	1750
193712	0.4005	190
193709	0.2919	104
193711	0.2388	77

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.36	gold quality
oocyte	CL:0000023	96.69	gold quality
left testis	UBERON:0004533	95.22	gold quality
right testis	UBERON:0004534	95.09	gold quality
testis	UBERON:0000473	94.30	gold quality
sural nerve	UBERON:0015488	92.57	gold quality
cortical plate	UBERON:0005343	92.00	gold quality
sperm	CL:0000019	91.54	gold quality
cerebellar cortex	UBERON:0002129	91.14	gold quality
cerebellar hemisphere	UBERON:0002245	91.12	gold quality
cerebellum	UBERON:0002037	90.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.74	gold quality
cerebellar vermis	UBERON:0004720	90.72	gold quality
ventricular zone	UBERON:0003053	90.65	gold quality
ganglionic eminence	UBERON:0004023	90.63	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.58	gold quality
tibial nerve	UBERON:0001323	90.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.36	gold quality
right ovary	UBERON:0002118	90.33	gold quality
mucosa of stomach	UBERON:0001199	90.18	gold quality
left ovary	UBERON:0002119	90.18	gold quality
male germ cell	CL:0000015	90.17	gold quality
gastrocnemius	UBERON:0001388	90.17	gold quality
popliteal artery	UBERON:0002250	90.13	gold quality
tibial artery	UBERON:0007610	90.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.12	gold quality
lower esophagus	UBERON:0013473	90.11	gold quality
muscle of leg	UBERON:0001383	90.02	gold quality
body of uterus	UBERON:0009853	90.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	yes	525.67
E-ANND-3	yes	6.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting EIF4ENIF1, 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-3924	100.00	72.09	2394
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-23B-5P	99.98	66.07	587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-589-3P	99.91	69.62	2088
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948

Literature-anchored findings (GeneRIF, showing 14)

• human P bodies contain the cap-binding protein eIF4E and the related factor eIF4E-transporter (eIF4E-T), suggesting novel roles for these proteins in targeting mRNAs for 5’ –> 3’ degradation (PMID:15840819)
• A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay is described. (PMID:16157702)
• Overexpression of eIF4E-T triggers the movement of eIF4E into the processing bodies. (PMID:18343217)
• Hsp90 probably contributes to the correct localization of eIF4E and 4E-T to stress granules and also to the interaction between eIF4E and eIF4G, both of which may be needed for eIF4E to acquire the physiological functionality (PMID:19850929)
• The c-Jun N-terminal kinase (JNK) is targeted to processing bodies in response to oxidative stress and promotes the phosphorylation of 4E-T. (PMID:22966201)
• Data demonstrate that EIF4ENIF1 is associated with dominantly inherited primary ovarian insufficiency. (PMID:23902945)
• that while both eIF4E1 and eIF4E2 bind 4E-T via the canonical YX 4Lvarphi sequence, nearby downstream sequences also influence eIF4E:4E-T interactions (PMID:23991149)
• This work has demonstrated the conserved yet unpredicted and surprising translational control of bound mRNAs by 4E-T, which does not involve eIF4E, nor P-body components. (PMID:24335285)
• neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic proteins to determine appropriate neurogenesis. (PMID:25456498)
• our data support a model where 4E-T promotes mRNA turnover by physically linking the 3’-terminal mRNA decay machinery to the 5’ cap (PMID:26027925)
• we demonstrate that joint deletion of two short conserved motifs that bind UNR and DDX6 relieves repression of 4E-T-bound mRNA, in part reliant on the 4E-T-DDX6-CNOT1 axis. (PMID:27342281)
• EIF4ENIF1 variants in two patients with non-syndromic premature ovarian insufficiency. (PMID:36030004)
• An intramolecular disulphide bond in human 4E-T affects its binding to eIF4E1a protein. (PMID:37798395)
• POI-associated EIF4ENIF1 mutations exhibit impaired translation regulation abilities. (PMID:38604507)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Eif4enif1	ENSMUSG00000020454
rattus_norvegicus	Eif4enif1	ENSRNOG00000018475
drosophila_melanogaster	cup	FBGN0000392
drosophila_melanogaster	4E-T	FBGN0052016

Protein

Protein identifiers

Eukaryotic translation initiation factor 4E transporter — Q9NRA8 (reviewed: Q9NRA8)

Alternative names: Eukaryotic translation initiation factor 4E nuclear import factor 1

All UniProt accessions (6): Q9NRA8, B0QYZ7, B1AKL4, B1AKL5, B1AKL6, H7C0J7

UniProt curated annotations — full annotation on UniProt →

Function. EIF4E-binding protein that regulates translation and stability of mRNAs in processing bodies (P-bodies). Plays a key role in P-bodies to coordinate the storage of translationally inactive mRNAs in the cytoplasm and prevent their degradation. Acts as a binding platform for multiple RNA-binding proteins: promotes deadenylation of mRNAs via its interaction with the CCR4-NOT complex, and blocks decapping via interaction with eIF4E (EIF4E and EIF4E2), thereby protecting deadenylated and repressed mRNAs from degradation. Component of a multiprotein complex that sequesters and represses translation of proneurogenic factors during neurogenesis. Promotes miRNA-mediated translational repression. Required for the formation of P-bodies. Involved in mRNA translational repression mediated by the miRNA effector TNRC6B by protecting TNRC6B-targeted mRNAs from decapping and subsequent decay. Also acts as a nucleoplasmic shuttling protein, which mediates the nuclear import of EIF4E and DDX6 by a piggy-back mechanism.

Subunit / interactions. Interacts (via YXXXXLphi motif) with EIF4E. Interacts (via YXXXXLphi motif) with EIF4E2. Interacts with DDX6. Interacts with CSDE1/UNR. Interacts with CNOT1; promoting association with the CCR4-NOT complex. Interacts with LSM14A; promoting EIF4ENIF1 localization to P-bodies. Interacts with PATL1. Interacts with importin beta only in the presence of importin alpha, suggesting a direct interaction with importin alpha. Interacts with APOBEC3G in an RNA-dependent manner.

Subcellular location. Cytoplasm. P-body. Nucleus. PML body. Nucleus speckle.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylation by MAPK8/JNK1 and or MAPK9/JNK2 in response to oxidative stress promotes P-body assembly. Phosphorylated during meiotic maturation.

Domain organisation. Intrinsically disordered protein with multiple low-complexity regions that confer binding to multiple RNA translation, deadenylation and decapping factors. The YXXXXLphi motif mediates interaction with eIF4E (EIF4E and EIF4E2).

Similarity. Belongs to the 4E-T/EIF4E-T family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NRA8-1	1	yes
Q9NRA8-2	2
Q9NRA8-3	3

RefSeq proteins (3): NP_001157973, NP_001157974, NP_062817* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018862	eIF4E-T	Family

Pfam: PF10477

UniProt features (70 total): modified residue 20, mutagenesis site 19, region of interest 10, helix 5, short sequence motif 4, compositionally biased region 4, splice variant 3, sequence conflict 2, chain 1, cross-link 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5ANR	X-RAY DIFFRACTION	2.1
6X2R	X-RAY DIFFRACTION	2.3
6F9W	X-RAY DIFFRACTION	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRA8-F1	51.15	0.02

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 (21): 5, 74, 78, 115, 120, 136, 138, 301, 345, 353, 374, 417, 486, 513, 564, 587, 693, 752, 920, 951 …

Mutagenesis-validated functional residues (19):

Position	Phenotype
30–36	abolished interaction with eif4e2.
30	abolishes interaction with eif4e and eif4e2. impaired ability to repress mrna translation.
35–36	abolished interaction with eif4e2.
54–61	strongly reduced interaction with eif4e and eif4e2.
195–196	abolishes the nuclear localization.
301	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
374	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
513	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
587	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
693	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
752	in s6a mutant; abolished phosphorylation by mapk8/jnk1; impaired p-body assembly in response to oxidative stress when as
955–958	abolished interaction with lsm14a.
958	abolished interaction with lsm14a.
959	abolished interaction with lsm14a.
961	does not affect interaction with lsm14a.
970	does not affect interaction with lsm14a.
978–981	abolished interaction with lsm14a.
978	abolished interaction with lsm14a.
982	abolished interaction with lsm14a.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 214 (showing top): GCM_MAP4K4, GOBP_P_BODY_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GCM_ZNF198, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_TRANSLATION, GOBP_NUCLEAR_TRANSPORT

GO Biological Process (15): translation (GO:0006412), protein import into nucleus (GO:0006606), negative regulation of translation (GO:0017148), stem cell population maintenance (GO:0019827), neuron differentiation (GO:0030182), P-body assembly (GO:0033962), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), negative regulation of neuron differentiation (GO:0045665), mRNA stabilization (GO:0048255), positive regulation of nuclear-transcribed mRNA poly(A) tail shortening (GO:0060213), negative regulation of deadenylation-dependent decapping of nuclear-transcribed mRNA (GO:0106289), regulation of translation (GO:0006417), protein transport (GO:0015031), regulatory ncRNA-mediated gene silencing (GO:0031047), nuclear export (GO:0051168)

GO Molecular Function (5): RNA binding (GO:0003723), mRNA binding (GO:0003729), nuclear export signal receptor activity (GO:0005049), kinase binding (GO:0019900), protein binding (GO:0005515)

GO Cellular Component (8): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), PML body (GO:0016605), nuclear speck (GO:0016607), cytoplasmic ribonucleoprotein granule (GO:0036464)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
translation	2
negative regulation of gene expression	2
negative regulation of mRNA catabolic process	2
cytoplasm	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
regulation of translation	1
negative regulation of protein metabolic process	1
multicellular organismal process	1
maintenance of cell number	1
cell differentiation	1
generation of neurons	1
membraneless organelle assembly	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
regulation of mRNA stability	1
RNA stabilization	1
nuclear-transcribed mRNA poly(A) tail shortening	1
regulation of nuclear-transcribed mRNA poly(A) tail shortening	1
positive regulation of mRNA catabolic process	1
deadenylation-dependent decapping of nuclear-transcribed mRNA	1
regulation of deadenylation-dependent decapping of nuclear-transcribed mRNA	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1

Protein interactions and networks

STRING

2979 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4ENIF1	EIF4E	P06730	997
EIF4ENIF1	DDX6	P26196	985
EIF4ENIF1	LSM14A	Q8ND56	928
EIF4ENIF1	NGDN	Q8NEJ9	793
EIF4ENIF1	PATL1	Q86TB9	778
EIF4ENIF1	PUM2	Q8TB72	739
EIF4ENIF1	LSM14B	Q9BX40	725
EIF4ENIF1	CPEB1	Q9BZB8	719
EIF4ENIF1	EDC4	Q6P2E9	713
EIF4ENIF1	PATL2	C9JE40	713
EIF4ENIF1	DCP1A	Q9NPI6	711
EIF4ENIF1	TNRC6A	Q8NDV7	676
EIF4ENIF1	EIF4G1	Q04637	672
EIF4ENIF1	EDC3	Q96F86	669
EIF4ENIF1	LSM1	O15116	623

IntAct

201 interactions, top by confidence:

A	B	Type	Score
EIF4E	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.940
EIF4ENIF1	EIF4E	psi-mi:“MI:0915”(physical association)	0.940
EIF4ENIF1	EIF4E	psi-mi:“MI:0914”(association)	0.940
EIF4E	EIF4ENIF1	psi-mi:“MI:0403”(colocalization)	0.940
DDX6	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.880
EIF4E2	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.830
EIF4E	EIF4G3	psi-mi:“MI:0914”(association)	0.810
EIF4E2	GIGYF2	psi-mi:“MI:0914”(association)	0.750
EIF4E2	GIGYF1	psi-mi:“MI:0914”(association)	0.730
EIF4ENIF1	EFHC1	psi-mi:“MI:0915”(physical association)	0.720
EFHC1	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (415): EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Two-hybrid), DTX2 (Two-hybrid), EFHC1 (Two-hybrid), MGAT5B (Two-hybrid), TXLNA (Two-hybrid), EIF4ENIF1 (Affinity Capture-MS), EIF4ENIF1 (Two-hybrid), EIF4ENIF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WPF7, A0A0R4IBL7, O09000, O54972, O70305, O75081, O75376, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P98180, Q05AQ8, Q14157, Q14687, Q1LY51, Q2VPM4, Q3U3C9, Q4KKX4, Q4VCS5, Q566L4, Q5F3B1, Q5SFM8, Q5T6F2, Q60722, Q60974, Q61286, Q62655, Q6DIH5, Q7ZWN6, Q7ZXS3, Q80X50, Q86YP4, Q8BZ47, Q8CHY6, Q8IXK0, Q8VHG2

Diamond homologs: Q9EST3, Q9NRA8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MAPK8	up-regulates	EIF4ENIF1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 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
Anchoring of the basal body to the plasma membrane	7	9.1×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
stress granule assembly	5	24.3×	5e-04
translational initiation	7	20.2×	2e-05
negative regulation of translation	11	17.4×	3e-08
mRNA transport	6	12.7×	1e-03
positive regulation of translation	6	11.0×	2e-03
cilium assembly	9	5.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	140
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3322 predictions. Top by Δscore:

Variant	Effect	Δscore
22:31440117:CAGAA:C	acceptor_gain	1.0000
22:31440120:AAC:A	acceptor_loss	1.0000
22:31440121:ACT:A	acceptor_loss	1.0000
22:31440122:C:CC	acceptor_gain	1.0000
22:31440122:CT:C	acceptor_loss	1.0000
22:31440123:T:G	acceptor_loss	1.0000
22:31441958:C:CA	donor_gain	1.0000
22:31442991:CTG:C	donor_gain	1.0000
22:31442992:TGT:T	donor_gain	1.0000
22:31443090:GAAAG:G	acceptor_gain	1.0000
22:31443091:AAAG:A	acceptor_gain	1.0000
22:31443092:AAG:A	acceptor_gain	1.0000
22:31443093:AG:A	acceptor_gain	1.0000
22:31443095:C:CC	acceptor_gain	1.0000
22:31444605:CCATG:C	donor_gain	1.0000
22:31444691:C:CC	acceptor_gain	1.0000
22:31447421:TTTAC:T	donor_loss	1.0000
22:31447423:TAC:T	donor_loss	1.0000
22:31447424:A:AC	donor_gain	1.0000
22:31447425:C:CA	donor_loss	1.0000
22:31447425:C:CC	donor_gain	1.0000
22:31447564:ATCTG:A	acceptor_gain	1.0000
22:31447565:TCTG:T	acceptor_loss	1.0000
22:31447566:CTG:C	acceptor_gain	1.0000
22:31447566:CTGC:C	acceptor_loss	1.0000
22:31447567:TG:T	acceptor_gain	1.0000
22:31447568:GC:G	acceptor_loss	1.0000
22:31447569:C:CC	acceptor_gain	1.0000
22:31447569:CT:C	acceptor_loss	1.0000
22:31447570:T:A	acceptor_loss	1.0000

AlphaMissense

6406 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:31443080:A:C	F696L	1.000
22:31443080:A:T	F696L	1.000
22:31443082:A:G	F696L	1.000
22:31454205:A:G	F484S	1.000
22:31463015:A:G	L235P	1.000
22:31463015:A:T	L235Q	1.000
22:31463021:A:T	I233N	1.000
22:31463056:C:A	W221C	1.000
22:31463056:C:G	W221C	1.000
22:31463058:A:G	W221R	1.000
22:31463058:A:T	W221R	1.000
22:31463893:A:G	C125R	1.000
22:31463903:A:C	F121L	1.000
22:31463903:A:T	F121L	1.000
22:31463905:A:G	F121L	1.000
22:31468277:A:G	W66R	1.000
22:31468277:A:T	W66R	1.000
22:31468290:C:A	W61C	1.000
22:31468290:C:G	W61C	1.000
22:31468292:A:G	W61R	1.000
22:31468292:A:T	W61R	1.000
22:31471910:A:G	L35P	1.000
22:31439961:A:C	F959L	0.999
22:31439961:A:T	F959L	0.999
22:31439962:A:G	F959S	0.999
22:31439963:A:G	F959L	0.999
22:31439964:C:A	W958C	0.999
22:31439964:C:G	W958C	0.999
22:31439966:A:G	W958R	0.999
22:31439966:A:T	W958R	0.999

dbSNP variants (sampled 300 via entrez): RS1000046900 (22:31449137 C>A,T), RS1000108240 (22:31485790 G>C), RS1000129182 (22:31449945 G>A), RS1000153835 (22:31493421 G>A,C,T), RS1000174500 (22:31455445 C>A,T), RS1000361263 (22:31477806 G>C), RS1000370481 (22:31461477 T>TC), RS1000382588 (22:31480054 T>G), RS1000541383 (22:31444089 C>T), RS1000549926 (22:31467190 G>A), RS1000611391 (22:31455651 G>A,C,T), RS1000653266 (22:31461295 A>G), RS1000798435 (22:31474949 A>G), RS1000823659 (22:31487354 C>T), RS1000869588 (22:31437735 G>A)

Disease associations

OMIM: gene MIM:607445 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ovarian failure	Moderate	Autosomal dominant

Mondo (1): primary ovarian failure (MONDO:0005387)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002491_24	Age-related hearing impairment	7.000000e-06
GCST010135_20	Oily fish consumption	3.000000e-10
GCST010135_5	Oily fish consumption	1.000000e-15
GCST010140_12	Pork consumption	3.000000e-10
GCST010140_49	Pork consumption	1.000000e-15
GCST010142_11	Fish- and plant-related diet	1.000000e-11
GCST010142_79	Fish- and plant-related diet	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	increases reaction, decreases response to substance, increases abundance, increases expression, affects binding (+1 more)	2
Arsenic	affects methylation, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
bisphenol A	affects expression	1
manganese chloride	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
CGP 57380	affects binding, decreases reaction, increases reaction	1
Air Pollutants	increases abundance, increases expression	1
Benzene	increases expression	1
Caffeine	affects phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	increases abundance, increases expression	1
Phthalic Acids	decreases methylation	1
Ribonucleotides	affects binding	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
Vitamin K 3	affects expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0VK	Ubigene Huh-7 EIF4ENIF1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists