NHSL3

Summary

NHSL3 (NHS like 3, HGNC:29301) is a protein-coding gene on chromosome 1p35.1, encoding NHS-like protein 3 (Q9P206). Able to directly activate the TNF-NFkappaB signaling pathway.

Predicted to be involved in cell differentiation.

Source: NCBI Gene 57648 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 242 total
• MANE Select transcript: NM_020888

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29301
Approved symbol	NHSL3
Name	NHS like 3
Location	1p35.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162522
Ensembl biotype	protein_coding
Entrez	57648

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000294521, ENST00000373480, ENST00000373481, ENST00000401073, ENST00000468130, ENST00000963201, ENST00000963202

RefSeq mRNA: 4 — MANE Select: NM_020888 NM_001198972, NM_001198973, NM_001369553, NM_020888

CCDS: CCDS41298, CCDS55588, CCDS55589, CCDS90910

Canonical transcript exons

ENST00000401073 — 7 exons

Exon	Start	End
ENSE00001066023	32768652	32768775
ENSE00001168910	32772865	32774970
ENSE00001208902	32769880	32772441
ENSE00001605906	32741830	32742189
ENSE00002173436	32769673	32769786
ENSE00003565099	32768062	32768117
ENSE00003567985	32767787	32767957

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.2449 / max 410.7789, expressed in 1674 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2009	16.6533	1102
2005	10.2008	1580
2006	0.9907	584
2008	0.8709	512
2007	0.8176	483
2003	0.7230	481
2004	0.5821	376
2017	0.4188	228
2015	0.4050	244
2016	0.3975	220

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	97.69	gold quality
upper arm skin	UBERON:0004263	97.31	gold quality
nasal cavity epithelium	UBERON:0005384	97.01	gold quality
right adrenal gland cortex	UBERON:0035827	96.88	gold quality
lower esophagus mucosa	UBERON:0035834	96.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.64	gold quality
right adrenal gland	UBERON:0001233	96.53	gold quality
left adrenal gland cortex	UBERON:0035825	96.50	gold quality
left adrenal gland	UBERON:0001234	96.21	gold quality
adrenal cortex	UBERON:0001235	96.09	gold quality
mucosa of transverse colon	UBERON:0004991	95.49	gold quality
body of pancreas	UBERON:0001150	94.87	gold quality
kidney epithelium	UBERON:0004819	94.86	silver quality
right uterine tube	UBERON:0001302	94.78	gold quality
esophagus mucosa	UBERON:0002469	94.78	gold quality
skin of leg	UBERON:0001511	94.73	gold quality
skin of abdomen	UBERON:0001416	94.68	gold quality
adrenal gland	UBERON:0002369	94.59	gold quality
saliva-secreting gland	UBERON:0001044	94.48	gold quality
minor salivary gland	UBERON:0001830	94.42	gold quality
palpebral conjunctiva	UBERON:0001812	94.11	gold quality
zone of skin	UBERON:0000014	94.01	gold quality
mouth mucosa	UBERON:0003729	93.84	gold quality
body of stomach	UBERON:0001161	93.83	gold quality
bronchial epithelial cell	CL:0002328	93.33	gold quality
metanephros cortex	UBERON:0010533	93.21	gold quality
parotid gland	UBERON:0001831	93.08	gold quality
bronchus	UBERON:0002185	92.99	gold quality
metanephros	UBERON:0000081	92.73	gold quality
pancreatic ductal cell	CL:0002079	92.56	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.16
E-CURD-53	no	211.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

125 targeting NHSL3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-373-3P	99.84	70.68	1668

Literature-anchored findings (GeneRIF, showing 5)

• high expression of KIAA1522 can be used as an independent biomarker for predication of poor survival and platinum-resistance of NSCLC patients, and aberrant KIAA1522 might be a new target for the therapy of the disease. (PMID:27098511)
• miR-125b-5p functions as a tumor suppressor and regulates breast cancer cell progression through targeting KIAA1522 (PMID:30177391)
• KIAA1522 potentiates TNFalpha-NFkappaB signaling to antagonize platinum-based chemotherapy in lung adenocarcinoma. (PMID:32854746)
• HOXA cluster antisense RNA 2 elevates KIAA1522 expression through microRNA-520d-3p and insulin like growth factor 2 mRNA binding protein 3 to promote the growth of vascular smooth muscle cells in thoracic aortic aneurysm. (PMID:35730141)
• Transcription factor KLF9 inhibits the proliferation, invasion, and migration of pancreatic cancer cells by repressing KIAA1522. (PMID:38520660)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhsl3	ENSDARG00000061804
mus_musculus	Nhsl3	ENSMUSG00000050390
rattus_norvegicus	Nhsl3	ENSRNOG00000008113

Paralogs (3): NHSL1 (ENSG00000135540), NHS (ENSG00000188158), NHSL2 (ENSG00000204131)

Protein

Protein identifiers

NHS-like protein 3 — Q9P206 (reviewed: Q9P206)

All UniProt accessions (1): Q9P206

UniProt curated annotations — full annotation on UniProt →

Function. Able to directly activate the TNF-NFkappaB signaling pathway.

Tissue specificity. Expressed in lung.

Disease relevance. Genetic variation involving NHSL3 may be a cause of atypical endothelial corneal dystrophy (ECD). The disease follows an autosomal dominant pattern of inheritance in the identified patients. Clinical characteristics of patients with the atypical form of ECD include peripheral endothelial opacities, an opaque ring along limbus, central endothelial opacities, central stromal opacities and corneal edema. The early phenotype of this atypical ECD is characterized by multiple small white translucent spots located in the Descemet membrane of the peripheral cornea.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P206-1	1	yes
Q9P206-2	2
Q9P206-3	3
Q9P206-4	4

RefSeq proteins (4): NP_001185901, NP_001185902, NP_001356482, NP_065939* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024845	NHS-like	Family

Pfam: PF15273

UniProt features (67 total): modified residue 30, compositionally biased region 19, sequence variant 7, region of interest 5, splice variant 3, chain 1, initiator methionine 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P206-F1	49.38	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 (31): 93, 138, 145, 161, 162, 215, 320, 322, 327, 330, 338, 339, 341, 342, 400, 404, 409, 531, 545, 593 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 144 (showing top): GGGACCA_MIR133A_MIR133B, MODULE_255, MODULE_317, AATGGAG_MIR136, PATIL_LIVER_CANCER, RICKMAN_METASTASIS_DN, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, LIAO_METASTASIS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, CAGCCTC_MIR4855P, SENESE_HDAC3_TARGETS_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, MODULE_69

GO Biological Process (1): cell differentiation (GO:0030154)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular developmental process	1
binding	1

Protein interactions and networks

STRING

970 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHSL3	POGK	Q9P215	403
NHSL3	FBXW10B	O95170	403
NHSL3	FLYWCH2	Q96CP2	391
NHSL3	GMPPA	Q96IJ6	375
NHSL3	TMEM167A	Q8TBQ9	370
NHSL3	NHSL1	Q5SYE7	361
NHSL3	TMEM245	Q9H330	358
NHSL3	AREL1	O15033	356
NHSL3	MEGF9	Q9H1U4	355
NHSL3	RRP36	Q96EU6	352
NHSL3	AHDC1	Q5TGY3	344
NHSL3	PLCXD2	Q0VAA5	337
NHSL3	SLC22A14	Q9Y267	333
NHSL3	TSNAXIP1	Q2TAA8	329
NHSL3	ORMDL2	Q53FV1	316

IntAct

78 interactions, top by confidence:

A	B	Type	Score
BAIAP2	YWHAZ	psi-mi:“MI:0914”(association)	0.800
BAIAP2	YWHAQ	psi-mi:“MI:0914”(association)	0.740
AFDN	YWHAH	psi-mi:“MI:0914”(association)	0.740
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
VASP	CEP43	psi-mi:“MI:0914”(association)	0.740
PKMYT1	CCNB2	psi-mi:“MI:0914”(association)	0.730
NCKAP1	YWHAH	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLMAP	STRN	psi-mi:“MI:2364”(proximity)	0.710
NHSL3	NCK1	psi-mi:“MI:0915”(physical association)	0.660
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
PPP2R3A	WTIP	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
NHSL3	NCK2	psi-mi:“MI:0914”(association)	0.530
EPS8L1	DHPS	psi-mi:“MI:0914”(association)	0.530
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
SFRP1	NHSL3	psi-mi:“MI:0915”(physical association)	0.370
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350

BioGRID (161): KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS), KIAA1522 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZM56, A2AG50, A2AI08, A2AJI0, A5D7K1, D4A4L4, E1C2Q8, F1LR10, O00515, O14529, O75128, O88573, O88735, P51825, P57016, Q14244, Q32LQ1, Q3KQU3, Q3U2K0, Q5JTD0, Q5NBX1, Q5PR69, Q5R7F9, Q5XHX2, Q5ZIA2, Q5ZJJ1, Q68DK7, Q6IPM2, Q6NV74, Q6NZF1, Q6PDH0, Q6PDM1, Q6PG95, Q6ZU35, Q86UU1, Q8CCJ4, Q8K124, Q8N7J2, Q8TD55, Q96PV7

Diamond homologs: A2A7S8, Q1LWM5, Q9P206, Q5SYE7, Q8CAF4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
Activation of BAD and translocation to mitochondria	7	75.1×	1e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	66.2×	2e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	66.2×	2e-10
Activation of BH3-only proteins	7	49.0×	2e-09
RHO GTPases Activate WASPs and WAVEs	10	44.7×	3e-12
RHO GTPases activate PKNs	8	35.7×	2e-09
Parasite infection	7	34.1×	3e-08
Leishmania phagocytosis	7	34.1×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
actin polymerization or depolymerization	5	42.1×	3e-05
Rac protein signal transduction	6	37.0×	4e-06
positive regulation of actin filament polymerization	6	21.8×	6e-05
protein targeting	5	20.1×	6e-04
regulation of protein localization	5	11.3×	5e-03
neuron migration	6	8.8×	4e-03
intracellular protein localization	7	8.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	223
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1665 predictions. Top by Δscore:

Variant	Effect	Δscore
1:32742187:GAG:G	donor_gain	1.0000
1:32742189:GGTA:G	donor_loss	1.0000
1:32742191:T:G	donor_loss	1.0000
1:32767785:A:AG	acceptor_gain	1.0000
1:32767786:G:GG	acceptor_gain	1.0000
1:32767953:CCAAG:C	donor_gain	1.0000
1:32767956:AG:A	donor_gain	1.0000
1:32767956:AGGT:A	donor_loss	1.0000
1:32767957:GG:G	donor_gain	1.0000
1:32767957:GGT:G	donor_loss	1.0000
1:32767958:G:GG	donor_gain	1.0000
1:32767958:GTA:G	donor_loss	1.0000
1:32768650:A:AG	acceptor_gain	1.0000
1:32768651:G:GT	acceptor_gain	1.0000
1:32768651:GT:G	acceptor_gain	1.0000
1:32768651:GTC:G	acceptor_gain	1.0000
1:32768771:CAAAG:C	donor_loss	1.0000
1:32768772:AAAG:A	donor_loss	1.0000
1:32768775:GG:G	donor_loss	1.0000
1:32768776:G:A	donor_loss	1.0000
1:32768777:T:G	donor_loss	1.0000
1:32769659:C:CA	acceptor_gain	1.0000
1:32769663:T:A	acceptor_gain	1.0000
1:32769668:CCCAG:C	acceptor_loss	1.0000
1:32769671:A:AG	acceptor_gain	1.0000
1:32769671:AGGC:A	acceptor_loss	1.0000
1:32769672:G:GG	acceptor_gain	1.0000
1:32769780:GAGC:G	donor_gain	1.0000
1:32769782:GCTTG:G	donor_gain	1.0000
1:32769783:C:G	donor_gain	1.0000

AlphaMissense

6885 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:32769681:T:C	F140L	0.999
1:32769682:T:C	F140S	0.999
1:32769682:T:G	F140C	0.999
1:32769683:C:A	F140L	0.999
1:32769683:C:G	F140L	0.999
1:32767937:T:C	L70P	0.997
1:32767913:T:C	L62P	0.996
1:32770243:T:C	I296T	0.996
1:32770923:A:C	S523R	0.996
1:32770925:T:A	S523R	0.996
1:32770925:T:G	S523R	0.996
1:32767924:G:C	A66P	0.995
1:32767946:T:C	L73P	0.995
1:32769681:T:A	F140I	0.995
1:32769681:T:G	F140V	0.995
1:32770252:C:A	A299D	0.995
1:32770927:G:A	G524E	0.995
1:32770935:A:C	S527R	0.995
1:32770937:C:A	S527R	0.995
1:32770937:C:G	S527R	0.995
1:32768769:C:A	R135S	0.994
1:32770227:T:G	Y291D	0.994
1:32770231:T:C	L292P	0.994
1:32767876:T:C	F50L	0.993
1:32767878:C:A	F50L	0.993
1:32767878:C:G	F50L	0.993
1:32767925:C:A	A66D	0.993
1:32767933:G:A	G69R	0.993
1:32767933:G:C	G69R	0.993
1:32770210:T:A	I285N	0.993

dbSNP variants (sampled 300 via entrez): RS1000007393 (1:32768532 T>G), RS1000135523 (1:32758374 G>A,C), RS1000181902 (1:32741820 G>A), RS1000262958 (1:32771846 G>A), RS1000284953 (1:32741704 G>A), RS1000292446 (1:32766043 A>G), RS1000301398 (1:32746274 A>G), RS1000354192 (1:32747702 C>A,T), RS1000368408 (1:32754712 C>G,T), RS1000446335 (1:32760681 C>T), RS1000635750 (1:32747898 C>T), RS1000662464 (1:32748087 G>T), RS1000687909 (1:32748171 T>A,C), RS1000899439 (1:32740681 G>C), RS1001291770 (1:32774524 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010988_526	Adult body size	5.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Acetaminophen	decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
butyraldehyde	decreases expression	1
coumarin	affects phosphorylation	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
(+)-JQ1 compound	decreases expression	1
mono(carboxy-isooctyl)phthalate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Quercetin	decreases phosphorylation	1
Smoke	decreases expression	1
Sodium Chloride	affects cotreatment, affects localization, decreases expression, increases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	decreases expression	1
Genistein	decreases expression	1

Clinical trials (associated diseases)

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