NHS

Chr X

NHS actin remodeling regulator

Also known as: CTRCT40, CXN

NCBI Gene: 4810 ENSG00000188158 UniProt: Q6T4R5

The NHS protein regulates actin remodeling and cell morphology, and controls development of the eye, teeth, brain, and craniofacial structures. Mutations cause Nance-Horan syndrome and X-linked cataract, both following X-linked inheritance patterns. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.087), indicating that mutations typically have significant developmental consequences.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNance-Horan syndrome

UniProtCataract 40

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Nance-Horan syndrome · XL · ClinGen 2017

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

5140

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — NHS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.42

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.82Z-score

OE missense 0.79 (0.74–0.86)

495 obs / 623.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.79 (0.74–0.86)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 34.1Missense obs/exp: 495 / 623.0Syn Z: 1.30

Background carrier burden — how many people carry a rare variant somewhere in NHS?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 53

1,207 rare PASS variants

Rare truncating (LoF)

1 in 6,700

25 rare PASS variants

Rare synonymous (reference)

1 in 89

521 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NHS. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 69	1 in 8,800
South Asian	~36k	1 in 40	≈ 1 in 17,000
Remaining (unassigned)	~31k	1 in 48	≈ 1 in 31,000
European (Finnish)	~27k	1 in 260	none seen
Admixed American	~23k	1 in 44	1 in 3,900
African / African American	~21k	1 in 46	≈ 1 in 4,900
East Asian	~20k	1 in 53	1 in 2,100
Ashkenazi Jewish	~13k	1 in 440	none seen
Middle Eastern	~2,758	1 in 74	≈ 1 in 2,700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓