NHS

Summary

NHS (NHS actin remodeling regulator, HGNC:7820) is a protein-coding gene on chromosome Xp22.2-p22.13, encoding Actin remodeling regulator NHS (Q6T4R5). May function in cell morphology by maintaining the integrity of the circumferential actin ring and controlling lamellipod formation. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein containing four conserved nuclear localization signals. The encoded protein functions in eye, tooth, craniofacial and brain development, and it can regulate actin remodeling and cell morphology. Mutations in this gene have been shown to cause Nance-Horan syndrome, and also X-linked cataract-40. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 4810 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Nance-Horan syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 861 total — 65 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 39
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001291867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7820
Approved symbol	NHS
Name	NHS actin remodeling regulator
Location	Xp22.2-p22.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188158
Ensembl biotype	protein_coding
OMIM	300457
Entrez	4810

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 4 retained_intron

ENST00000380060, ENST00000398097, ENST00000485305, ENST00000615422, ENST00000617601, ENST00000648929, ENST00000676302, ENST00000690213, ENST00000690608

RefSeq mRNA: 4 — MANE Select: NM_001291867 NM_001136024, NM_001291867, NM_001291868, NM_198270

CCDS: CCDS14181, CCDS48087, CCDS94562

Canonical transcript exons

ENST00000676302 — 9 exons

Exon	Start	End
ENSE00001366686	17725347	17728328
ENSE00001369847	17692335	17692468
ENSE00001377602	17724299	17724430
ENSE00001381759	17687742	17687894
ENSE00001383248	17728649	17728775
ENSE00001483598	17731858	17735994
ENSE00001483599	17719344	17719406
ENSE00003519777	17721441	17721633
ENSE00003902656	17375200	17376322

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 96.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.1462 / max 176.7821, expressed in 977 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195668	1.4452	722
195667	1.1617	592
195671	0.2743	108
195670	0.1251	42
209616	0.0895	28
209617	0.0503	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	96.66	gold quality
buccal mucosa cell	CL:0002336	92.66	gold quality
endothelial cell	CL:0000115	90.64	gold quality
kidney epithelium	UBERON:0004819	84.85	silver quality
epithelial cell of pancreas	CL:0000083	84.64	silver quality
palpebral conjunctiva	UBERON:0001812	83.08	gold quality
visceral pleura	UBERON:0002401	82.76	gold quality
germinal epithelium of ovary	UBERON:0001304	82.68	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.52	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.17	gold quality
caput epididymis	UBERON:0004358	81.28	gold quality
endometrium	UBERON:0001295	80.80	gold quality
pigmented layer of retina	UBERON:0001782	80.77	gold quality
esophagus squamous epithelium	UBERON:0006920	80.17	gold quality
descending thoracic aorta	UBERON:0002345	80.13	gold quality
middle temporal gyrus	UBERON:0002771	79.98	gold quality
thoracic aorta	UBERON:0001515	79.82	gold quality
ascending aorta	UBERON:0001496	79.77	gold quality
cauda epididymis	UBERON:0004360	79.63	gold quality
bronchial epithelial cell	CL:0002328	79.20	gold quality
parietal pleura	UBERON:0002400	78.94	gold quality
bronchus	UBERON:0002185	78.27	gold quality
aorta	UBERON:0000947	78.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.07	gold quality
calcaneal tendon	UBERON:0003701	78.04	gold quality
seminal vesicle	UBERON:0000998	77.85	gold quality
fallopian tube	UBERON:0003889	77.44	gold quality
tibia	UBERON:0000979	76.91	gold quality
uterus	UBERON:0000995	76.91	gold quality
tibial artery	UBERON:0007610	76.83	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	73.42
E-CURD-119	yes	44.16
E-HCAD-25	yes	40.89
E-ANND-3	no	5.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting NHS, 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-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
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-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• key functions in the regulation of eye, tooth, brain, and craniofacial development (PMID:14564667)
• independent identification of the gene (NHS)causative for Nance-Horan syndrome and extends the number of mutations identified (PMID:15466011)
• X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. (PMID:15623749)
• We demonstrate the differential expression of the two NHS isoforms, NHS-A and NHS-1A, and differences in the subcellular localization of the proteins encoded by these isoforms. (PMID:16675532)
• identification of the frequency and distribution of NHS gene mutations and comparison of genotype with Nance-Horan phenotype in five North American NHS families; this report extends the number of unique identified NHS mutations to 14 (PMID:17417607)
• This study aimed to identify the causative mutations in new patients diagnosed with Nance-Horan syndrome and to investigate the effect of mutations on subcellular localization of the NHS-A protein. (PMID:18949062)
• Four novel protein truncation mutations and a large deletion of the NHS gene lead to Nance-Horan syndrome. (PMID:19414485)
• these data identify NHS as a new regulator of actin remodelling. (PMID:20332100)
• Direct sequencing of NHS sequences in a Tunisian family identified the first missense mutation (P551S) and a reported SNP-polymorphism (L1319F) in exon 6, a reported UTR-SNP (c.7422 C>T) and a novel one (c.8239 T>A) in exon 8. (PMID:21559051)
• Lens opacities centered around the posterior Y-suture in the context of certain facial features were sensitive and specific clinical signs of carrier status for NHS mutation in asymptomatic females. (PMID:22229851)
• Identification of a previously unreported frameshift mutation (c.558insA) in exon 1 of the NHS gene in a Turkish family with Nance-Horan Syndrome. (PMID:23566852)
• mutations in NHS are the common cause of congenital cataract (PMID:24968223)
• A nonsense mutation c.322G>T (E108X) co-segregated with the disease in a family. Multiple sequence alignments showed that codon 108, where the mutation (c.322G>T) occurred, was located within a phylogenetically conserved region. (PMID:25091991)
• Our findings broaden the spectrum of NHS mutations causing Nance-Horan syndrome and phenotypic spectrum of the disease in Chinese patients. (PMID:25266737)
• Results revealed a novel splice site mutation (NM_198270: c.1045 + 2T > A) in the 5’ consensus donor site of intron 4 in the NHS gene in a Chinese family. This mutation led to aberrantly spliced mRNA, which is likely to result in a truncated NHS protein. (PMID:28061824)
• Here, we report a microdeletion of 170,6 Kb at Xp22.13 (17.733.948-17.904.576) (GRCh37/hg19).The microdeletion harbors the NHS, SCLML1, and RAI2 genes and results in a phenotype consistent with Nance-Horan syndromesyndrome and developmental delay. (PMID:28464487)
• Our study expands the repertoire of NHS mutations and the related phenotype, including newly described anterior Y-sutural cataract and dental findings. (PMID:28557584)
• This is the first report of Nance-Horan syndrome due to a skewed X chromosome inactivation resulting from a balanced translocation t(X;1) that disrupts the NHS gene expression, with important implications for clinical presentation and genetic counseling. (PMID:28922055)
• A novel small deletion in the NHS gene is associated with Nance-Horan syndrome in a Chinese pedigree. (PMID:29402928)
• Nance-Horan syndrome (NHS) is an X-linked inheritance disorder characterized by bilateral congenital cataracts, and facial and dental dysmorphism. This disorder is caused by mutations in the NHS gene. However, NHS may be difficult to detect in individuals with subtle facial dysmorphism and dental abnormalities in whom congenital cataracts are the primary clinical manifestations. (PMID:30642278)
• Deleterious NHS mutations are associated with Nance Horan syndrome. (PMID:31755796)
• Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline. (PMID:32303606)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhsa	ENSDARG00000070227
danio_rerio	nhsb	ENSDARG00000079977
mus_musculus	Nhs	ENSMUSG00000059493
rattus_norvegicus	Nhs	ENSRNOG00000030759

Paralogs (3): NHSL1 (ENSG00000135540), NHSL3 (ENSG00000162522), NHSL2 (ENSG00000204131)

Protein

Protein identifiers

Actin remodeling regulator NHS — Q6T4R5 (reviewed: Q6T4R5)

Alternative names: Congenital cataracts and dental anomalies protein, Nance-Horan syndrome protein

All UniProt accessions (3): A0A087WU78, A0A3B3ITB2, Q6T4R5

UniProt curated annotations — full annotation on UniProt →

Function. May function in cell morphology by maintaining the integrity of the circumferential actin ring and controlling lamellipod formation. Involved in the regulation eye, tooth, brain and craniofacial development.

Subunit / interactions. Interacts with the tight junction protein TJP1/ZO-1. Associates with actin-rich structures. Interacts with BRK1 and with all three members of the WAVE protein family, WASF1, WASF2 and WASF3.

Subcellular location. Apical cell membrane. Cell projection. Lamellipodium. Cell junction. Tight junction. Focal adhesion Cytoplasm.

Tissue specificity. Detected at low levels in all tissues analyzed. Detected in fetal and adult brain, lens, retina, retinal pigment epithelium, placenta, lymphocytes and fibroblasts. Levels in retinal pigment epithelium, placenta, lymphocytes, and fibroblasts are very low. Expressed also in kidney, lung and thymus.

Disease relevance. Nance-Horan syndrome (NHS) [MIM:302350] Rare X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, intellectual disability. Distinctive dental anomalies are seen in affected males, including supernumerary incisors and crown shaped permanent teeth. Characteristic facial features are anteverted pinnae, long face, and prominent nasal bridge and nose. Carrier females display milder variable symptoms of disease with lens opacities often involving the posterior Y sutures, and on occasion dental anomalies and the characteristic facial features described. The disease is caused by variants affecting the gene represented in this entry. Cataract 40 (CTRCT40) [MIM:302200] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT40 manifests as a congenital nuclear opacity with severe visual impairment in affected males. Heterozygous females have suture cataracts and only slight reduction in vision. In some cases, cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. The disease is caused by variants affecting the gene represented in this entry. Caused by copy number variations predicted to result in altered transcriptional regulation of the NHS gene: a 0.8 Mb segmental duplication-triplication encompassing the NHS, SCML1 and RAI2 genes, and an 4.8 kb intragenic deletion in NHS intron 1.

Similarity. Belongs to the NHS family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q6T4R5-1	1, NHS-A	yes
Q6T4R5-2	2
Q6T4R5-3	3, NHS-1A
Q6T4R5-4	4

RefSeq proteins (4): NP_001129496, NP_001278796, NP_001278797, NP_938011 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024845	NHS-like	Family

Pfam: PF15273

UniProt features (47 total): compositionally biased region 13, region of interest 12, modified residue 9, sequence variant 6, splice variant 5, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6T4R5-F1	43.65	0.04

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 (9): 332, 401, 415, 533, 739, 1176, 1262, 1329, 1499

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle

MSigDB gene sets: 223 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, ATGCTGG_MIR338, GOCC_APICAL_PLASMA_MEMBRANE, AACTTT_UNKNOWN, TGAGATT_MIR216, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, CCAGGTT_MIR490, CCCAGAG_MIR326, GOBP_SENSORY_ORGAN_DEVELOPMENT, ATGTCAC_MIR489, GOCC_CELL_CELL_JUNCTION, CTTTGTA_MIR524

GO Biological Process (2): lens development in camera-type eye (GO:0002088), cell differentiation (GO:0030154)

GO Molecular Function (0):

GO Cellular Component (12): Golgi apparatus (GO:0005794), bicellular tight junction (GO:0005923), focal adhesion (GO:0005925), apical plasma membrane (GO:0016324), nuclear body (GO:0016604), lamellipodium (GO:0030027), cell junction (GO:0030054), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
camera-type eye development	1
anatomical structure development	1
cellular developmental process	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
apical junction complex	1
tight junction	1
cell-substrate junction	1
apical part of cell	1
plasma membrane region	1
nucleoplasm	1
intracellular membraneless organelle	1
cell leading edge	1
plasma membrane bounded cell projection	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

876 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHS	RAI2	Q9Y5P3	952
NHS	GCNT2	Q8N0V5	768
NHS	CDKL5	O76039	685
NHS	IL17C	Q9P0M4	557
NHS	SCP2	P22307	542
NHS	MIB1	Q86YT6	458
NHS	TRIP11	Q15643	415
NHS	HSF1	Q00613	393
NHS	CANX	P27824	374
NHS	HEMK2	Q9Y5N5	349
NHS	GJE1	A6NN92	322
NHS	GJC3	Q8NFK1	307
NHS	MAFF	Q9ULX9	297
NHS	AMY2B	P19961	281
NHS	AMY1B	P04745	273

IntAct

36 interactions, top by confidence:

A	B	Type	Score
BRK1	HSBP1	psi-mi:“MI:0914”(association)	0.740
NCKAP1	YWHAH	psi-mi:“MI:0914”(association)	0.730
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
NHSL3	NCK2	psi-mi:“MI:0914”(association)	0.530
KXD1	TRAK2	psi-mi:“MI:0914”(association)	0.530
NCKAP1	NHSL1	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
P/V/C	KPNA3	psi-mi:“MI:0914”(association)	0.530
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350
Otud5	MROH1	psi-mi:“MI:0914”(association)	0.350
KIF5B	TRAK1	psi-mi:“MI:0914”(association)	0.350
USP43	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
KIFC3	CC2D1B	psi-mi:“MI:0914”(association)	0.350
Mllt1	ELL2	psi-mi:“MI:0914”(association)	0.350
Sesn2	CASTOR2	psi-mi:“MI:0914”(association)	0.350
CENPU	CENPX	psi-mi:“MI:0914”(association)	0.350
ABI1	NHSL1	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
NCKAP1	ENAH	psi-mi:“MI:0914”(association)	0.350
ABI2	NCKAP1L	psi-mi:“MI:0914”(association)	0.350
ABI3	TBKBP1	psi-mi:“MI:0914”(association)	0.350
FSD2	MYO9A	psi-mi:“MI:0914”(association)	0.350
P/V/C	KPNA3	psi-mi:“MI:0914”(association)	0.350
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
PTPRU	ARHGAP5	psi-mi:“MI:2364”(proximity)	0.270
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (58): NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS), NHS (Affinity Capture-MS)

ESM2 similar proteins: A2A9F4, A5PLN7, A6H7B4, A6NJJ6, A8K5M9, B1AXH1, B2RQL2, B5G1P1, B5X7E4, O35182, O95886, P0CAX8, P97838, Q00587, Q08DN6, Q0VBZ8, Q17QW1, Q1LZ80, Q2KIL8, Q2TBN9, Q3KP66, Q5M865, Q5RBE4, Q60664, Q68FX5, Q6AY88, Q6AYH0, Q6DJE5, Q6PFD5, Q6T4R5, Q7TN12, Q80U35, Q80U49, Q80VC9, Q8BFY7, Q8CE97, Q8NAX2, Q8WYL5, Q91XA5, Q96EL1

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NHS	up-regulates	Actin_cytoskeleton_reorganization
NHS	“up-regulates activity”	ARP2/3	relocalization
BRK1	“up-regulates activity”	NHS	binding
CYFIP1	“up-regulates activity”	NHS	binding
NCKAP1	“up-regulates activity”	NHS	binding
NHS	“up-regulates activity”	“WRC complex”	relocalization
NHS	“up-regulates activity”	ABI2	binding
TJP1	“up-regulates activity”	NHS	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 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	148.0×	6e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	130.6×	1e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	130.6×	1e-12
Activation of BH3-only proteins	7	96.5×	1e-11
RHO GTPases activate PKNs	7	61.7×	4e-10
Parasite infection	6	57.7×	1e-08
Leishmania phagocytosis	6	57.7×	1e-08
Intrinsic Pathway for Apoptosis	7	56.9×	6e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	7	59.6×	7e-09
intracellular protein localization	7	17.0×	3e-05
cell migration	6	8.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	65
Likely pathogenic	18
Uncertain significance	319
Likely benign	158
Benign	74

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070594	NM_001291867.2(NHS):c.3979_3982del (p.Ser1327fs)	Pathogenic
1070979	NM_001291867.2(NHS):c.1159C>T (p.Gln387Ter)	Pathogenic
11023	NM_001291867.2(NHS):c.2450dup (p.Ser818fs)	Pathogenic
11024	NM_001291867.2(NHS):c.3522del (p.Leu1175fs)	Pathogenic
11025	NM_001291867.2(NHS):c.1180C>T (p.Arg394Ter)	Pathogenic
11026	NM_001291867.2(NHS):c.718+1dup	Pathogenic
11027	NM_001291867.2(NHS):c.115C>T (p.Gln39Ter)	Pathogenic
11028	NM_001291867.2(NHS):c.916-2A>G	Pathogenic
11029	NCBI36/hg18 Xp22.13(chrX:17104696-17800261)x3	Pathogenic
1323364	NM_001291867.2(NHS):c.1237del (p.Glu412_Ile413insTer)	Pathogenic
1363083	NM_001291867.2(NHS):c.916-2A>T	Pathogenic
1446464	NM_001291867.2(NHS):c.50_53del (p.Arg17fs)	Pathogenic
1452872	NM_001291867.2(NHS):c.766dup (p.Leu256fs)	Pathogenic
1458715	NM_001291867.2(NHS):c.4315C>T (p.Arg1439Ter)	Pathogenic
1460128	NC_000023.10:g.(?17710435)(17750584_?)del	Pathogenic
167352	NM_001291867.2(NHS):c.565+1G>T	Pathogenic
167357	NM_001291867.2(NHS):c.2633del (p.Gly878fs)	Pathogenic
190248	NM_001291867.2(NHS):c.852+1del	Pathogenic
1996935	NM_001291867.2(NHS):c.3021del (p.Phe1007fs)	Pathogenic
1998013	NM_001291867.2(NHS):c.1084del (p.Cys362fs)	Pathogenic
217326	NM_001291867.2(NHS):c.2770del (p.Glu924fs)	Pathogenic
217352	NM_001291867.2(NHS):c.3687C>A (p.Cys1229Ter)	Pathogenic
2427646	NC_000023.10:g.(?17705842)(17710608_?)del	Pathogenic
2574153	NM_001291867.2(NHS):c.853-2A>C	Pathogenic
2574154	NM_001291867.2(NHS):c.3801_3802del (p.Ala1268fs)	Pathogenic
2694921	NM_001291867.2(NHS):c.134dup (p.Asp45fs)	Pathogenic
2698992	NM_001291867.2(NHS):c.86del (p.Gly29fs)	Pathogenic
2766965	NM_001291867.2(NHS):c.372dup (p.Cys125fs)	Pathogenic
2769541	NM_001291867.2(NHS):c.2897C>A (p.Ser966Ter)	Pathogenic
2851377	NM_001291867.2(NHS):c.3307_3323del (p.His1103fs)	Pathogenic

SpliceAI

3520 predictions. Top by Δscore:

Variant	Effect	Δscore
X:17376319:GTGC:G	donor_gain	1.0000
X:17500183:GA:G	donor_gain	1.0000
X:17523934:C:G	donor_gain	1.0000
X:17674953:G:T	donor_gain	1.0000
X:17687740:A:AG	acceptor_gain	1.0000
X:17687741:G:GG	acceptor_gain	1.0000
X:17687741:GCC:G	acceptor_gain	1.0000
X:17692467:CGGT:C	donor_loss	1.0000
X:17692468:GGT:G	donor_loss	1.0000
X:17692470:T:G	donor_loss	1.0000
X:17721439:A:AG	acceptor_gain	1.0000
X:17721440:G:GA	acceptor_gain	1.0000
X:17721440:GTCCC:G	acceptor_gain	1.0000
X:17721597:G:GG	donor_gain	1.0000
X:17728647:A:G	acceptor_gain	1.0000
X:17728772:ACAG:A	donor_loss	1.0000
X:17728774:AG:A	donor_loss	1.0000
X:17728775:GGT:G	donor_loss	1.0000
X:17728776:GTGAG:G	donor_loss	1.0000
X:17376313:G:GT	donor_gain	0.9900
X:17376321:GC:G	donor_gain	0.9900
X:17376323:G:GG	donor_gain	0.9900
X:17397659:GC:G	donor_gain	0.9900
X:17496744:A:G	acceptor_gain	0.9900
X:17500184:A:G	donor_gain	0.9900
X:17658102:G:GT	donor_gain	0.9900
X:17674888:G:GT	donor_gain	0.9900
X:17687736:TTGCA:T	acceptor_loss	0.9900
X:17687737:TGCA:T	acceptor_loss	0.9900
X:17687738:GCA:G	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000021820 (X:17685924 AG>A), RS1000024469 (X:17569512 G>A), RS1000033212 (X:17685543 A>G), RS1000035386 (X:17538677 G>A,T), RS1000052311 (X:17407466 G>C), RS1000053251 (X:17521477 C>T), RS1000073216 (X:17507968 T>C), RS1000089906 (X:17435457 C>G), RS1000105158 (X:17520602 G>C), RS1000123947 (X:17715301 C>A,G,T), RS1000129371 (X:17636151 A>G), RS1000155287 (X:17382342 C>T), RS1000171399 (X:17634574 C>G), RS1000175897 (X:17720213 C>T), RS1000178592 (X:17503120 G>T)

Disease associations

OMIM: gene MIM:300457 | disease phenotypes: MIM:302350, MIM:302200, MIM:309510

GenCC curated gene-disease

Disease	Classification	Inheritance
Nance-Horan syndrome	Definitive	X-linked
early-onset nuclear cataract	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Nance-Horan syndrome	Definitive	XL

Mondo (8): Nance-Horan syndrome (MONDO:0010545), cataract 40 (MONDO:0010544), intellectual disability (MONDO:0001071), prostate cancer (MONDO:0008315), coloboma (MONDO:0001476), X-linked syndromic intellectual disability (MONDO:0020119), lymphedema (MONDO:0019297), early-onset nuclear cataract (MONDO:0020376)

Orphanet (8): Nance-Horan syndrome (Orphanet:627), Early onset non-syndromic cataract (Orphanet:91492), Familial prostate cancer (Orphanet:1331), OBSOLETE: Ocular coloboma (Orphanet:194), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: X-linked syndromic intellectual disability (Orphanet:98464), OBSOLETE: Lymphedema (Orphanet:79383)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000164	Abnormality of the dentition
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000541	Retinal detachment
HP:0000568	Microphthalmia
HP:0000572	Visual loss
HP:0000639	Nystagmus
HP:0000689	Dental malocclusion
HP:0000699	Diastema
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0001141	Severely reduced visual acuity
HP:0001249	Intellectual disability
HP:0001417	X-linked inheritance
HP:0001423	X-linked dominant inheritance
HP:0001500	Broad finger
HP:0002342	Moderate intellectual disability
HP:0003577	Congenital onset
HP:0006332	Supernumerary maxillary incisor

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008209	Lymphedema	C15.604.496
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C563333	Cataract, Age-Related Nuclear (supp.)
C535338	Cataract, congenital, with microcornea or slight microphthalmia (supp.)
C538336	Nance-Horan syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	3
graphene oxide	increases expression	2
bisphenol A	decreases expression, decreases methylation	2
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	2
Cisplatin	affects cotreatment, decreases expression	2
Estradiol	decreases expression, decreases reaction, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Asbestos, Crocidolite	increases expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
hydroxyhydroquinone	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	increases expression	1
Calcitriol	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders