NHS

protein-coding

NHS actin remodeling regulator, the group of MicroRNA protein coding host genes

Gene summary

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. [provided by RefSeq, May 2014]

MANE transcript

NM_001291867.2

Inheritance

XL, AD

ClinVar variants

P:94U:433B:293

Top phenotype

Nance-Horan syndrome; Cataract 40

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:17,375,200-17,735,994

External References & Databases

Ensembl (ENSG00000188158)

Transcript & Mutation Effects

hg38 • Region Span ~360.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Nance-Horan syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: Labcorp Genetics (formerly Invitae)

early-onset nuclear cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020376

Submitter: Orphanet

Nance-Horan syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: Orphanet

Nance-Horan syndromeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: Ambry Genetics

Nance-Horan syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: PanelApp Australia

Nance-Horan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: G2P

Nance-Horan syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010545

Submitter: ClinGen

*NHS* was first reported in relation to X-linked Nance-Horan syndrome in 2003 (Burdon et al., PMID: 14564667). *NHS* encodes a protein that is essential for normal embryonic development and acts as a regulator of actin remodeling. Nance-Horan syndrome is characterized by congenital cataracts with microcornea, dental abnormalities, facial dysmorphism, and in some patients, intellectual disability and autism spectrum disorder. Female carriers may be asymptomatic or exhibit milder features, such as lens opacities, mild facial dysmorphism, and characteristic dental abnormalities. Five variants (nonsense, frameshift, splice) that have been reported in six probands in two publications (PMIDs: 14564667, 18949062) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model with cataracts (PMID: 16357105) and functional alterations in non-patient cells (PMID: 20332100). In summary, there is definitive evidence supporting the relationship between *NHS* and X-linked Nance-Horan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.

Clinical Genomic Database (CGD)

Nance-Horan syndrome; Cataract 40XL

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 4470901; 458526; 11836358; 14564667; 15623749; 16736028; 17256798; 19414485; 20882036; 25266737

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHS variants in ClinVar

16 Conditions Cataloged

Nance-Horan syndromeTotal: 452

Inborn genetic diseasesTotal: 211

not providedTotal: 203

not specifiedTotal: 78

NHS-related disorderTotal: 73

Cataract 40Total: 20

Intellectual disabilityTotal: 11

Bilateral congenital or childhood onset cataractsTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001291867.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			46 clinvar	140 clinvar	27 clinvar	213
missense	1 clinvar		367 clinvar	102 clinvar	23 clinvar	493
nonsense	19 clinvar	8 clinvar	7 clinvar			34
start loss						0
frameshift	33 clinvar	25 clinvar	1 clinvar	1 clinvar		60
splice donor/acceptor (+/-2bp)	5 clinvar	3 clinvar	12 clinvar			20
Total	58	36	433	243	50	820

Highest pathogenic variant AF is 9.10615e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001291867.2	RefSeq	NP_001278796.1	9	MANE Select
ENST00000676302.1	Ensembl	ENSP00000502262.1	9	MANE Select
NM_001136024.4	RefSeq	NP_001129496.1	9	Standard
NM_001291868.2	RefSeq	NP_001278797.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

lens development in camera-type eye
cell differentiation

Cellular Component

Golgi apparatus
bicellular tight junction
focal adhesion
apical plasma membrane
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380060
Coding exons: 8
Length: 360572
Individuals with no LoFs: 120940
Homozygous LoFs: 1
Heterozygous LoFs: 1
Defined: 120942
p: 0.00000827

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.82	495	623	0.795	0.0000505	10612
Missense (PolyPhen)		196	297.75	0.65828		4898
Synonymous	1.30	221	247	0.895	0.0000203	3406
Loss of Function	5.42	0	34.1	0.00	0.00000278	600

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000025	0.000019	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:20332100}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:19414485}. Note=The disease is caused by mutations 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.;

Recessive Scores

pRec: 0.148

Intolerance Scores

RVIS EVS: -0.73
RVIS percentile EVS: 14.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0565

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium