PLAC1

Summary

PLAC1 (placenta enriched 1, HGNC:9044) is a protein-coding gene on chromosome Xq26.3, encoding Placenta-specific protein 1 (Q9HBJ0). May play a role in placental development.

Involved in placenta development. Predicted to be located in extracellular region.

Source: NCBI Gene 10761 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_021796

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9044
Approved symbol	PLAC1
Name	placenta enriched 1
Location	Xq26.3
Locus type	gene with protein product
Status	Approved
Aliases	CT92, OOSP2L, OOSP2B
Ensembl gene	ENSG00000170965
Ensembl biotype	protein_coding
OMIM	300296
Entrez	10761

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000359237, ENST00000466797, ENST00000473897, ENST00000476971, ENST00000878501, ENST00000917137, ENST00000917138, ENST00000917139, ENST00000950374

RefSeq mRNA: 4 — MANE Select: NM_021796 NM_001316887, NM_001316888, NM_001316889, NM_021796

CCDS: CCDS14642

Canonical transcript exons

ENST00000359237 — 3 exons

Exon	Start	End
ENSE00001153676	134602051	134602122
ENSE00001153689	134658328	134658471
ENSE00001424097	134565838	134566740

Expression profiles

Bgee: expression breadth ubiquitous, 105 present calls, max score 92.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3357 / max 184.3673, expressed in 100 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200586	0.2579	68
200585	0.0519	39
200587	0.0259	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	92.17	gold quality
adrenal tissue	UBERON:0018303	88.15	gold quality
oocyte	CL:0000023	86.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.67	gold quality
secondary oocyte	CL:0000655	79.94	gold quality
cartilage tissue	UBERON:0002418	70.67	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.80	gold quality
stromal cell of endometrium	CL:0002255	62.80	gold quality
pancreatic ductal cell	CL:0002079	61.86	silver quality
decidua	UBERON:0002450	59.34	gold quality
endothelial cell	CL:0000115	55.78	gold quality
hair follicle	UBERON:0002073	55.71	gold quality
ileal mucosa	UBERON:0000331	54.49	silver quality
deltoid	UBERON:0001476	54.19	gold quality
lower esophagus mucosa	UBERON:0035834	54.17	gold quality
cerebellar vermis	UBERON:0004720	53.66	gold quality
right testis	UBERON:0004534	53.55	gold quality
amniotic fluid	UBERON:0000173	52.52	gold quality
buccal mucosa cell	CL:0002336	51.72	gold quality
testis	UBERON:0000473	51.72	gold quality
epithelial cell of pancreas	CL:0000083	51.52	gold quality
quadriceps femoris	UBERON:0001377	49.90	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
left testis	UBERON:0004533	49.15	gold quality
metanephros	UBERON:0000081	49.02	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	57.29
E-ANND-3	yes	3.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, ESR1, NCOA1, NCOA2, NCOA3, NR1H3, SOX2, SP1, TP53

miRNA regulators (miRDB)

12 targeting PLAC1, 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-302E	99.96	70.74	2669
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-1178-3P	98.57	67.09	890

Literature-anchored findings (GeneRIF, showing 40)

• PLAC1, a trophoblast-specific gene, is Trophoblast-specific expression throughout gestation and responsiveness to KGF are consistent with a fundamental role for PLAC1 at the maternal-fetal interface. (PMID:12412044)
• mRNA transcripts from placenta-expressed specific gene are detectable in maternal blood and rapidly disappear after delivery (PMID:15608456)
• PLAC1 expression is upregulated during trophoblast differentiation, localizing primarily to the differentiated syncytiotrophoblast. (PMID:15803460)
• Plasma PLAC1 and glial cells-missing 1 mRNAs appear promising as noninvasively measurable molecular markers for pre-eclampsia (PMID:16594548)
• In induced term pregnancies, PLAC1 mRNA in maternal blood at the beginning of the treatment correlates with time elapsed before delivery; this demonstrates that fetomaternal trafficking of nucleic acids is more consistent when labor is about to begin. (PMID:16860456)
• Data show that PLAC1 is restricted primarily to the differentiated trophoblast, localizing to intracellular membranous compartment(s) in the apical region of the syncytiotrophoblast and associated with its apical, microvillous membrane surface. (PMID:17186554)
• CRH, PLAC1, and selectin-P are distributed differently in preeclampsia cases compared to controls and correlate with signs of preeclampsia. (PMID:17554801)
• RNAi-mediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G1-S cell cycle block with nearly complete abrogation of proliferation. (PMID:17909063)
• study demonstrated that PLAC1 is a novel tumor antigen with very restricted normal tissue expression; also evidence provided that PLAC1 is expressed in the tumor cells in a subset of lung cancer patients (PMID:17983203)
• 3.8% (4/101) of HCC patients had anti-PLAC1 antibody response, suggesting the immunogenicity of PLAC1 in HCC patients. PLAC1 represents a new class of tumor associated antigen with restricted expression in placenta and cancer tissues. (PMID:18183594)
• analysis of activation of trophoblast-specific PLAC1 in breast cancer by CCAAT/enhancer-binding protein beta (C/EBPbeta) isoform 2 (PMID:19652226)
• In normal tissues, PLAC1 expression was restricted to the placenta while developmental pluripotency associated-2 expression was restricted to the placenta and testis. (PMID:19705800)
• A potential role for PLAC1 as a biomarker predictive of specific pregnancy complications, such as preeclampsia. (PMID:20509147)
• The expression of PLAC1/CP1 genes correlates with various clinical and pathologic parameters in primary colorectal carcinoma. (PMID:21215095)
• A novel HLA-A2-restricted cytotoxic T lymphocyte epitope from cancer-testis antigen PLAC1 has been identified in breast cancer. (PMID:21710262)
• RXRalpha and LXR activate two promoters in placenta- and tumor-specific expression of PLAC1. (PMID:21937108)
• we identified a novel specific antitrophoblast antibody, anti-PLAC1, in infertile women with repeated unexplained implantation failure. PLAC1 shows placenta-specific expression and is localized primarily in the syncytiotrophoblast. (PMID:23434395)
• PLAC1/CP1 antigen is a possible prognostic marker of colorectal carcinoma, and PLAC1/CP1 p41-50 and PLAC1/CP1 p69-77 are novel HLA-A*0201-restricted CD8+ T cell epitopes (PMID:23604623)
• NCOA3 is a selective co-activator of estrogen receptor alpha-mediated transactivation of PLAC1. (PMID:24304549)
• This data suggests that the Epstein-Barr virus-induced PLAC1 is a member of the cancer/testis group of tumor antigens. (PMID:24912876)
• Data suggests that PLAC1 plays an important role in human placental trophoblast invasion and migration. (PMID:24989904)
• circulating mRNA improved detection rate of pre-eclampsia (PMID:25138310)
• PLAC1/CP1 provides a marker for identifying gastric cancers with poor prognosis, and suggest that PLAC1/CP1 may provide a useful target for immunotherapy. (PMID:26157147)
• PLAC1 was mainly expressed in the human villous syncytiotrophoblast (STB) layer throughout gestation, and the expression level of PLAC1 was significantly elevated during human trophoblast syncytialization. (PMID:27692364)
• Plac1 plays a pivotal role in the progression of HCC, and may serve as a novel therapeutic target for Hepatocellular carcinoma. (PMID:27878289)
• Optimized protocol for soluble prokaryotic expression, purification and structural analysis of human placenta specific-1(PLAC1). (PMID:28315746)
• we show that PLAC1 transcript number is significantly negatively correlated with patient survival in our samples. Thus, we suggest that characterizing tumors for TP53 mutation status, p53 protein status and PLAC1 transcription could be used to predict likely prognosis and inform treatment options in patients diagnosed with serous ovarian cancer. (PMID:28339050)
• this paper shows that PLAC1 immunization does not induce infertility in mice (PMID:28351180)
• This study demonstrated that the protein expression of PLAC1 was significantly associated with decreased overall survival in patients with pancreatic ductal adenocarcinoma, indicating that it was a valuable prognostic marker for pancreatic ductal adenocarcinoma and might be a potential target for immunotherapy. (PMID:28618924)
• Screening for these five CTAs and PLAC1 by RTqPCR may offer a potentially valuable prognostic tool with good sensitivity and specificity in patients with Hepatocellular carcinoma (HCC) that may be enhanced by magneticactivated cell sorting . (PMID:28849093)
• Study revealed that PLAC1 expression was highly expressed in non-small cell lung cancer (NSCLC) tissues, suggesting that PLAC1 may be a prognostic factor and higher risk for NSCLC patients. PLAC1 was involved in regulation of the proliferation, migration, and invasion abilities of NSCLC cells partly through regulation of epithelial-mesenchymal transition and the AKT pathway. (PMID:29138842)
• There was no significant correlation of serum PLAC1 levels with race, age at diagnosis, body mass index (BMI) or the presence of metastatic disease. It remains to be determined whether PLAC1 serum levels can serve as a diagnostic biomarker for the presence or recurrence of disease post-surgery and/or therapy (PMID:29432428)
• The findings suggest a possible pathophysiological link between the development of Fetal growth restriction and the expression of PAPPA, PAPPA2 and PLAC-1. (PMID:29532882)
• These findings suggest that functional interaction between Plac1 and Furin enhances breast cancer invasion and metastasis and the Furin/Notch1 intracellular domain (NICD) /PTEN axis may act as an important therapeutic target for breast cancer treatment. (PMID:29704427)
• Placenta-specific protein 1 enhances liver metastatic potential and is associated with the PI3K/AKT/NF-kappaB signaling pathway in colorectal cancer. (PMID:32701605)
• High expression of PLAC1 in colon cancer as a predictor of poor prognosis: A study based on TCGA data. (PMID:32827679)
• Plac1 promotes nasopharyngeal carcinoma cells proliferation, migration and invasion via Furin/NICD/PTEN pathway. (PMID:33418237)
• Expression of placenta-specific 1 and its potential for eliciting anti-tumor helper T-cell responses in head and neck squamous cell carcinoma. (PMID:33457076)
• PLAC1 Regulates the Occurrence of Fetal Growth Restriction by Inhibiting the Apoptosis of Trophoblast Cells. (PMID:33941557)
• Expression level of PLAC1 in osteosarcoma patients and its regulatory effect on the development of osteosarcoma. (PMID:34077010)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Plac1	ENSMUSG00000061082
rattus_norvegicus	Plac1	ENSRNOG00000002379

Paralogs (2): OOSP2 (ENSG00000149507), OOSP1 (ENSG00000284873)

Protein

Protein identifiers

Placenta-specific protein 1 — Q9HBJ0 (reviewed: Q9HBJ0)

All UniProt accessions (1): Q9HBJ0

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in placental development.

Subcellular location. Secreted.

Tissue specificity. Expressed in placenta. Localizes primarily to differentiated syncytiotrophoblast throughout gestation as well as to a small population of villous cytotrophoblasts. Also detected in maternal blood and rapidly disappears following delivery, but is not detected in other adult or fetal tissues examined.

Induction. Up-regulated during trophoblast differentiation and by FGF7 in trophoblast cells.

Similarity. Belongs to the PLAC1 family.

RefSeq proteins (4): NP_001303816, NP_001303817, NP_001303818, NP_068568* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033222	PLAC1_fam	Family
IPR055356	ZP-N	Domain

Pfam: PF23344

UniProt features (2 total): signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBJ0-F1	70.47	0.39

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 75 (showing top): GAANYNYGACNY_UNKNOWN, CAGCTG_AP4_Q5, EVI1_05, MARTINEZ_RB1_TARGETS_DN, GATA6_01, HEN1_01, GNF2_KISS1, GOBP_PLACENTA_DEVELOPMENT, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MARTINEZ_RB1_AND_TP53_TARGETS_UP, EVI1_03, GATA_Q6, SENESE_HDAC3_TARGETS_DN, TGGAAA_NFAT_Q4_01, AP1FJ_Q2

GO Biological Process (1): placenta development (GO:0001890)

GO Molecular Function (0):

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	1
cellular anatomical structure	1

Protein interactions and networks

STRING

506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLAC1	ZP3	P21754	885
PLAC1	HPRT1	P00492	718
PLAC1	PAPPA	Q13219	520
PLAC1	ZP1	P60852	491
PLAC1	KISS1	Q15726	476
PLAC1	GCM1	Q9NP62	473
PLAC1	MID1	O15344	466
PLAC1	PHF6	Q8IWS0	456
PLAC1	ADAM12	O43184	449
PLAC1	GPC3	P51654	448
PLAC1	PAPPA2	Q9BXP8	439
PLAC1	PRY	O14603	432
PLAC1	CRH	P06850	429
PLAC1	MTNAP1	Q9BSJ5	400
PLAC1	INSL4	Q14641	374

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PLAC1	OBSL1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
CGB5	IGSF3	psi-mi:“MI:0914”(association)	0.350
SLC25A14	PLOD3	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): EP400 (Affinity Capture-MS), MEAF6 (Affinity Capture-MS), EPC2 (Affinity Capture-MS), TRRAP (Affinity Capture-MS), BRD8 (Affinity Capture-MS), VPS72 (Affinity Capture-MS), ING3 (Affinity Capture-MS), DMAP1 (Affinity Capture-MS), OBSL1 (Affinity Capture-MS), EPC1 (Affinity Capture-MS), TADA1 (Affinity Capture-MS), MBTD1 (Affinity Capture-MS), MRGBP (Affinity Capture-MS), KAT5 (Affinity Capture-MS), YEATS4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YXX9, A0A1Z2R986, A0A2R8Y4Y8, A0A2R8YFL7, A0A2R8YFM6, A0A8J1K1A4, A6MFL5, A6MFL6, A6MFL7, A6NHS7, A8MZH6, F8RKW5, G5E8D7, O54767, O77726, O88393, P17219, P20239, P26342, P34128, P35054, P42099, P47983, P47984, P70041, Q03167, Q05996, Q07G34, Q14CH0, Q1W7Q6, Q2Q0J1, Q3HXY1, Q3HXY2, Q3HXY3, Q3HXY4, Q3HXY5, Q3HXY6, Q3HXY8, Q3HXZ1, Q4FZG8

Diamond homologs: A0A2R8YFL7, Q2Q0J1, Q9HBJ0, A0A2R8Y4Y8, A0A2R8YFM6, A8MZH6, Q4FZG8, Q4V7E2, Q86WS3, Q9JI83

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

643 predictions. Top by Δscore:

Variant	Effect	Δscore
X:134602046:CTAA:C	donor_loss	0.9900
X:134602047:TAA:T	donor_loss	0.9900
X:134602048:AAC:A	donor_loss	0.9900
X:134602049:A:T	donor_loss	0.9900
X:134602050:CCTTC:C	donor_loss	0.9900
X:134602123:C:CC	acceptor_gain	0.9900
X:134643789:A:AC	donor_gain	0.9900
X:134566741:C:CC	acceptor_gain	0.9800
X:134583781:T:A	donor_gain	0.9800
X:134602043:AAACT:A	donor_loss	0.9800
X:134602044:AACTA:A	donor_loss	0.9800
X:134602045:ACT:A	donor_loss	0.9800
X:134602120:CAG:C	acceptor_gain	0.9800
X:134602120:CAGCT:C	acceptor_loss	0.9800
X:134602122:GCT:G	acceptor_loss	0.9800
X:134602123:CT:C	acceptor_loss	0.9800
X:134602124:T:G	acceptor_loss	0.9800
X:134643760:T:A	donor_gain	0.9700
X:134643785:A:AC	donor_gain	0.9700
X:134643786:C:CC	donor_gain	0.9700
X:134643790:A:C	donor_gain	0.9700
X:134658323:CTTA:C	donor_loss	0.9700
X:134658324:TTACC:T	donor_loss	0.9700
X:134658325:TACCT:T	donor_loss	0.9700
X:134658326:A:C	donor_loss	0.9700
X:134658327:CCTG:C	donor_gain	0.9700
X:134658322:ACTT:A	donor_loss	0.9600
X:134658326:ACCTG:A	donor_gain	0.9600
X:134658327:CCTGC:C	donor_gain	0.9600
X:134566739:TT:T	acceptor_gain	0.9500

AlphaMissense

1417 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:134566465:A:G	F73S	0.994
X:134566464:G:C	F73L	0.985
X:134566464:G:T	F73L	0.985
X:134566466:A:G	F73L	0.985
X:134566444:C:G	C80S	0.984
X:134566445:A:T	C80S	0.984
X:134566465:A:C	F73C	0.983
X:134566403:A:C	Y94D	0.982
X:134566445:A:G	C80R	0.978
X:134566579:A:G	F35S	0.977
X:134566501:C:G	C61S	0.973
X:134566502:A:G	C61R	0.973
X:134566502:A:T	C61S	0.973
X:134566438:A:G	I82T	0.971
X:134566513:A:G	L57S	0.970
X:134566460:A:C	Y75D	0.967
X:134566594:C:G	C30S	0.965
X:134566595:A:T	C30S	0.965
X:134566340:A:G	C115R	0.961
X:134566511:C:G	G58R	0.961
X:134566443:A:C	C80W	0.959
X:134566592:A:G	S31P	0.959
X:134566339:C:G	C115S	0.958
X:134566340:A:T	C115S	0.958
X:134566444:C:A	C80F	0.958
X:134566511:C:A	G58C	0.958
X:134566573:A:T	V37D	0.958
X:134566466:A:C	F73V	0.957
X:134566510:C:A	G58V	0.957
X:134566519:A:G	L55P	0.957

dbSNP variants (sampled 300 via entrez): RS1000002593 (X:134573673 G>A), RS1000071479 (X:134672344 C>A), RS1000082839 (X:134745196 C>A), RS1000084419 (X:134660352 C>T), RS1000086268 (X:134678702 G>T), RS1000090527 (X:134590009 C>T), RS1000122897 (X:134647751 T>C), RS1000150953 (X:134665673 C>T), RS1000154763 (X:134732544 C>A), RS1000160756 (X:134665184 A>G), RS1000164811 (X:134756944 A>G), RS1000182980 (X:134639831 C>T), RS1000192552 (X:134599173 A>G), RS1000216313 (X:134734097 C>T), RS1000217680 (X:134742575 G>A,T)

Disease associations

OMIM: gene MIM:300296 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007557_1	Birth weight	1.000000e-09
GCST008161_113	Waist circumference adjusted for body mass index	3.000000e-07
GCST008362_135	Birth weight	3.000000e-14
GCST90002383_124	Hematocrit	7.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0007789	BMI-adjusted waist circumference
EFO:0004348	hematocrit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Estradiol	increases expression, increases reaction	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
titanium dioxide	increases expression	1
trichostatin A	increases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Wortmannin	decreases reaction, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	increases expression	1
Aldehydes	increases expression	1
Cadmium	increases abundance, increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Testosterone	affects cotreatment, increases expression, decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

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