RILP

Summary

RILP (Rab interacting lysosomal protein, HGNC:30266) is a protein-coding gene on chromosome 17p13.3, encoding Rab-interacting lysosomal protein (Q96NA2). Rab effector playing a role in late endocytic transport to degradative compartments.

This gene encodes a lysosomal protein that interacts with RAB7, a small GTPase that controls transport to endocytic degradative compartments. Studies using mutant forms of the two proteins suggest that this protein represents a downstream effector for RAB7, and both proteins act together in the regulation of late endocytic traffic. A unique region of this protein has also been shown to be involved in the regulation of lysosomal morphology.

Source: NCBI Gene 83547 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_031430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30266
Approved symbol	RILP
Name	Rab interacting lysosomal protein
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31193
Ensembl gene	ENSG00000167705
Ensembl biotype	protein_coding
OMIM	607848
Entrez	83547

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 retained_intron

ENST00000301336, ENST00000570858, ENST00000573398, ENST00000574810, ENST00000898468, ENST00000898469, ENST00000898470, ENST00000898471, ENST00000931214, ENST00000946792, ENST00000946793

RefSeq mRNA: 1 — MANE Select: NM_031430 NM_031430

CCDS: CCDS11009

Canonical transcript exons

ENST00000301336 — 8 exons

Exon	Start	End
ENSE00001198710	1648799	1649044
ENSE00001198713	1649200	1649306
ENSE00001198717	1649412	1649505
ENSE00001307433	1646150	1646619
ENSE00001312933	1649577	1649866
ENSE00003590495	1646906	1646989
ENSE00003596432	1647835	1647957
ENSE00003690521	1648350	1648495

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6203 / max 143.3783, expressed in 1662 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163759	3.6598	1349
163763	1.5084	371
163760	1.0293	598
163767	0.6591	247
163764	0.5697	195
163761	0.5361	232
163762	0.4188	176
163766	0.1485	51
163765	0.0904	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.87	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.02	gold quality
heart left ventricle	UBERON:0002084	94.83	gold quality
right lobe of thyroid gland	UBERON:0001119	93.36	gold quality
gastrocnemius	UBERON:0001388	92.72	gold quality
left lobe of thyroid gland	UBERON:0001120	92.44	gold quality
muscle of leg	UBERON:0001383	92.33	gold quality
thyroid gland	UBERON:0002046	92.00	gold quality
blood	UBERON:0000178	91.69	gold quality
right atrium auricular region	UBERON:0006631	91.67	gold quality
heart	UBERON:0000948	91.47	gold quality
mucosa of transverse colon	UBERON:0004991	91.30	gold quality
skeletal muscle tissue	UBERON:0001134	90.84	gold quality
right lobe of liver	UBERON:0001114	90.47	gold quality
duodenum	UBERON:0002114	90.18	gold quality
right adrenal gland cortex	UBERON:0035827	88.60	gold quality
liver	UBERON:0002107	88.33	gold quality
muscle tissue	UBERON:0002385	88.11	gold quality
left adrenal gland cortex	UBERON:0035825	88.06	gold quality
right adrenal gland	UBERON:0001233	87.95	gold quality
transverse colon	UBERON:0001157	87.58	gold quality
left adrenal gland	UBERON:0001234	87.50	gold quality
right lung	UBERON:0002167	87.00	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.59	gold quality
adipose tissue	UBERON:0001013	86.56	gold quality
omental fat pad	UBERON:0010414	86.53	gold quality
monocyte	CL:0000576	86.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.21	gold quality
upper lobe of left lung	UBERON:0008952	86.21	gold quality
spleen	UBERON:0002106	86.19	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting RILP, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-7112-5P	99.59	65.76	104
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-490-5P	96.75	65.81	661
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Literature-anchored findings (GeneRIF, showing 20)

• Unique region in RILP responsible for its specific role in regulating lysosomal morphology as well as in its interaction with Rab7 and Rab34. (PMID:14668488)
• The crystal structure of Rab7-GTP in complex with the Rab7 binding domain of RILP reveals that Rab7 interacts with RILP specifically via two distinct areas. (PMID:15933719)
• The data together indicate that RILP, as already demonstrated for several other Rab effector proteins, is capable of self-association, thus probably forming a homo-dimer. (PMID:15996637)
• RILP indeed prenylated, while phosphorylation analysis showed that the two protein kinase A sites are phosphorylated. (PMID:16417580)
• Hence, RILPsv provides an extra dimension to the control of vesicle fusion and transport by the small GTPase Rab7. (PMID:16631113)
• we have isolated, using the yeast two-hybrid system, the EAP30/SNF8/VPS22 subunit of the ESCRT-II complex as a RILP interacting protein. (PMID:16857164)
• These results establish that RILP is required for biogenesis of multivesicular endosomes and degradative trafficking of EGFRs but not for trafficking of transferrin receptors through early endosomes. (PMID:17959629)
• REST/NRSF, dynactin p150(Glued), huntingtin, HAP1, and RILP form a complex involved in the translocation of REST/NRSF into the nucleus and HAP1 controls REST/NRSF cellular localization in neurons (PMID:18922795)
• Results describe how ORP1L contacts VAP to control Rab7-RILP-p150 Glued and late endosome positioning. (PMID:19564404)
• RILP directly and concomitantly binds the tethering HOPS complex and the p150(Glued) subunit of the dynein motor. ORP1L then functions as a cholesterol-sensing switch controlling RILP-HOPS-p150(Glued) interactions. (PMID:23729732)
• RILP regulates the activity of the V-ATPase through its interaction with V1G1. (PMID:24762812)
• VPS41 subunit of HOPS complex was defined to be the major partner for interacting with RILP. (PMID:25445562)
• RILP regulates vacuolar ATPase through interaction with the V1G1 subunit (PMID:26180254)
• RILP suppresses the invasion of breast cancer cells by interacting with RalGDS to inhibit its guanine nucleotide exchange factor activity for RalA. (PMID:26469971)
• Hepatitis C virus (HCV) modifies cellular trafficking by cleaving Rab interacting lysosomal protein (RILP), which serves to redirect ras-related protein Rab-7 (Rab7)-containing vesicles to a kinesin-dependent trafficking mode promoting virion secretion. (PMID:27791088)
• structural and biochemical investigation of the Rab7-ORP1L interaction revealed architecture that leaves the canonical effector-interacting switch regions available for RILP binding and thus allows formation of the ORP1L-Rab7-RILP tripartite complex. (PMID:30012887)
• Caspase-1 regulates cellular trafficking via cleavage of the Rab7 adaptor protein RILP in cultured neoplastic epithelial cells has been reported. (PMID:30100068)
• Methylation of RILP in lung cancer promotes tumor cell proliferation and invasion. (PMID:33128214)
• RILP inhibits proliferation, migration, and invasion of PC3 prostate cancer cells. (PMID:35981451)
• RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions. (PMID:39195203)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rilp	ENSDARG00000074660
mus_musculus	Rilp	ENSMUSG00000038195
rattus_norvegicus	Rilp	ENSRNOG00000003784
drosophila_melanogaster	Rilpl	FBGN0024985
caenorhabditis_elegans		WBGENE00007860

Paralogs (4): DZIP1 (ENSG00000134874), RILPL2 (ENSG00000150977), DZIP1L (ENSG00000158163), RILPL1 (ENSG00000188026)

Protein

Protein identifiers

Rab-interacting lysosomal protein — Q96NA2 (reviewed: Q96NA2)

All UniProt accessions (2): Q96NA2, I3L1U0

UniProt curated annotations — full annotation on UniProt →

Function. Rab effector playing a role in late endocytic transport to degradative compartments. Involved in the regulation of lysosomal morphology and distribution. Induces recruitment of dynein-dynactin motor complexes to Rab7A-containing late endosome and lysosome compartments. Promotes centripetal migration of phagosomes and the fusion of phagosomes with the late endosomes and lysosomes.

Subunit / interactions. Homodimer. Interacts with RAB7A. Interacts with RAB34. Identified in a complex with MREG and DCTN1; interacts directly with MREG. Interacts with CLN3. Interacts with FLCN; the interaction is direct and promotes association between RILP and RAB34.

Subcellular location. Late endosome membrane. Lysosome membrane. Cytoplasmic vesicle. Phagosome membrane.

Tissue specificity. Ubiquitous. Strongly expressed in fetal heart, heart, stomach, spleen, adrenal gland, thyroid gland, salivary gland, fetal liver, liver and lung. Poorly expressed in brain.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96NA2-1	1	yes
Q96NA2-2	2

RefSeq proteins (1): NP_113618* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021563	RILP_dimer	Domain
IPR034743	RH1	Domain
IPR034744	RH2	Domain
IPR051241	DZIP_RILPL	Family

Pfam: PF09744, PF11461

UniProt features (27 total): mutagenesis site 8, modified residue 3, region of interest 3, domain 2, splice variant 2, sequence variant 2, helix 2, compositionally biased region 2, chain 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1YHN	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NA2-F1	71.72	0.38

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 (3): 314, 315, 308

Mutagenesis-validated functional residues (8):

Position	Phenotype
248	strongly reduces dimerization and localization to late endosomal/lysosomal compartments.
251	abolishes dimerization, interaction with rab7a and localization to late endosomal/lysosomal compartments.
252	abolishes interaction with rab7a and localization to late endosomal/lysosomal compartments.
255	abolishes dimerization, interaction with rab7a and localization to late endosomal/lysosomal compartments.
258	reduces dimerization, interaction with rab7a and localization to late endosomal/lysosomal compartments.
304	abolishes interaction with rab7a and localization to late endosomal/lysosomal compartments.
305	abolishes interaction with rab7a and localization to late endosomal/lysosomal compartments.
306	abolishes interaction with rab7a and localization to late endosomal/lysosomal compartments.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation

MSigDB gene sets: 108 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER

GO Biological Process (8): endosome to lysosome transport (GO:0008333), protein transport (GO:0015031), endosome transport via multivesicular body sorting pathway (GO:0032509), negative regulation of protein catabolic process (GO:0042177), early endosome to late endosome transport (GO:0045022), positive regulation of protein catabolic process (GO:0045732), cilium assembly (GO:0060271), intralumenal vesicle formation (GO:0070676)

GO Molecular Function (4): small GTPase binding (GO:0031267), protein dimerization activity (GO:0046983), dynein light intermediate chain binding (GO:0051959), protein binding (GO:0005515)

GO Cellular Component (11): cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), late endosome (GO:0005770), phagocytic vesicle membrane (GO:0030670), late endosome membrane (GO:0031902), protein-containing complex (GO:0032991), ciliary basal body (GO:0036064), endosome (GO:0005768), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein catabolic process	2
regulation of protein catabolic process	2
cytoplasm	2
endosome membrane	2
protein binding	2
cellular anatomical structure	2
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
endosomal transport	1
multivesicular body sorting pathway	1
negative regulation of catabolic process	1
negative regulation of protein metabolic process	1
vesicle-mediated transport between endosomal compartments	1
positive regulation of catabolic process	1
positive regulation of protein metabolic process	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
vesicle budding from membrane	1
endosome organization	1
GTPase binding	1
binding	1
intracellular anatomical structure	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
endosome	1
endocytic vesicle membrane	1
phagocytic vesicle	1
late endosome	1
cellular_component	1

Protein interactions and networks

STRING

743 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RILP	RAB34	Q9BZG1	922
RILP	RAB7A	P51149	788
RILP	DCTN1	Q14203	765
RILP	OSBPL1A	Q9BXW6	703
RILP	RDX	P35241	689
RILP	MSN	P26038	674
RILP	RAB36	O95755	656
RILP	RILPL2	Q969X0	623
RILP	FYCO1	Q9BQS8	619
RILP	EZR	P15311	588
RILP	MREG	Q8N565	587
RILP	ATP6V1G1	O75348	573
RILP	SNAP29	O95721	557
RILP	VAMP8	Q9BV40	552
RILP	ARL8B	Q9NVJ2	524

IntAct

44 interactions, top by confidence:

A	B	Type	Score
RILP	RAB7A	psi-mi:“MI:0407”(direct interaction)	0.930
RILP	RAB7A	psi-mi:“MI:0915”(physical association)	0.930
RAB7A	RILP	psi-mi:“MI:0915”(physical association)	0.930
EIF2S1	EIF2S3	psi-mi:“MI:0914”(association)	0.820
OSBPL1A	RAB7A	psi-mi:“MI:0915”(physical association)	0.670
RILP	VPS41	psi-mi:“MI:0915”(physical association)	0.570
RILP	VPS41	psi-mi:“MI:0403”(colocalization)	0.570
RILP	VPS41	psi-mi:“MI:0407”(direct interaction)	0.570
TGFBR2	RILP	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	RILP	psi-mi:“MI:0915”(physical association)	0.560
INSR	ACTB	psi-mi:“MI:0914”(association)	0.530
RILP	VPS16	psi-mi:“MI:0915”(physical association)	0.460
RILP	VPS18	psi-mi:“MI:0915”(physical association)	0.460
RILP	VPS11	psi-mi:“MI:0915”(physical association)	0.460
RILP	VPS39	psi-mi:“MI:0915”(physical association)	0.460
RILP	VPS18	psi-mi:“MI:0403”(colocalization)	0.460
VPS39	RILP	psi-mi:“MI:0403”(colocalization)	0.460
RILP	VPS16	psi-mi:“MI:0403”(colocalization)	0.460
RILP	VPS11	psi-mi:“MI:0403”(colocalization)	0.460
	RAB7A	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (41): RILP (Two-hybrid), VPS11 (Reconstituted Complex), VPS16 (Reconstituted Complex), VPS18 (Reconstituted Complex), VPS39 (Reconstituted Complex), VPS41 (Reconstituted Complex), RILP (Reconstituted Complex), RAB7A (Reconstituted Complex), RILP (Affinity Capture-MS), RAB7A (Affinity Capture-Western), RILP (Affinity Capture-Western), RAB7A (Affinity Capture-Western), RILP (Two-hybrid), RAB7A (Affinity Capture-Western), RILP (Two-hybrid)

ESM2 similar proteins: A0A140LIT1, A0A1B0GVG4, A0A494C0Y3, A0JNH6, A0JNN8, A1A5D9, A2ARS0, A5A769, A5PJP1, A6NC98, A7YWC8, C9JTQ0, O15049, O35764, O95502, P0C7N4, P0DPE3, P58660, Q0P5D1, Q1HCM0, Q2TAC2, Q3LUD3, Q3LUD4, Q3TMW1, Q3UMT1, Q4QRL3, Q5BLP8, Q5JTB6, Q6QNY0, Q6QZQ4, Q8BP01, Q8C7U1, Q8CHW5, Q8K262, Q8N283, Q8N6Y0, Q8TAT2, Q8TER5, Q8TF21, Q91XV7

Diamond homologs: A0PJT0, Q17QG3, Q5EBL4, Q5ND29, Q96NA2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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.

GO biological processes:

GO term	Partners	Fold	FDR
endosomal vesicle fusion	5	244.2×	2e-09
endosome to lysosome transport	6	87.9×	6e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2547 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:1648407:C:G	R255P	0.992
17:1648398:A:G	L258P	0.991
17:1647865:A:G	M305T	0.990
17:1649031:A:G	L148P	0.988
17:1649710:G:T	A32D	0.986
17:1649689:A:G	L39P	0.985
17:1647877:A:G	I301T	0.983
17:1648365:A:G	L269P	0.983
17:1649282:A:G	L116P	0.983
17:1649022:A:G	L151P	0.982
17:1649001:A:G	L158P	0.980
17:1648382:G:C	F263L	0.979
17:1648382:G:T	F263L	0.979
17:1648384:A:G	F263L	0.979
17:1648377:A:G	L265P	0.978
17:1648394:T:A	K259N	0.978
17:1648394:T:G	K259N	0.978
17:1649244:C:G	A129P	0.978
17:1647877:A:C	I301S	0.976
17:1649258:C:G	R124P	0.975
17:1646915:A:G	I340T	0.974
17:1648395:T:A	K259I	0.974
17:1649249:A:G	L127P	0.974
17:1649620:A:G	L62P	0.972
17:1647873:C:A	K302N	0.969
17:1647873:C:G	K302N	0.969
17:1647872:C:G	A303P	0.968
17:1647898:A:T	V294D	0.968
17:1648371:T:A	E267V	0.968
17:1648350:C:G	R274P	0.967

dbSNP variants (sampled 300 via entrez): RS1000325663 (17:1649427 G>A,T), RS1000464998 (17:1647198 G>A), RS1000532766 (17:1648243 T>C), RS1000648800 (17:1648011 T>C,G), RS1001010739 (17:1650260 C>G), RS1001289560 (17:1647276 A>G), RS1001590531 (17:1647510 GAAT>G), RS1002205595 (17:1647094 G>A), RS1002318513 (17:1646891 C>T), RS1002586045 (17:1645832 G>A,T), RS1002769236 (17:1650774 G>A), RS1004418082 (17:1649137 G>A,C), RS1004445334 (17:1649894 T>G), RS1004498685 (17:1650008 C>A,G), RS1004778492 (17:1648600 G>C)

Disease associations

OMIM: gene MIM:607848 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

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
Tobacco Smoke Pollution	decreases methylation, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
hydroxyhydroquinone	decreases expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
4-aminobenzhydrazide	decreases expression, decreases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Urethane	increases expression	1
Valproic Acid	decreases expression, increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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