# NM_001291867.2(NHS):c.3021del (p.Phe1007fs)

https://sugi.bio/variant/nhs-p-phe1007fs

## Summary

**NHS p.Phe1007fs (c.3021del)** is classified **Pathogenic** in NHS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-20). No gnomAD frequency available for this variant; Associated with Nance-Horan syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2519938991 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NHS gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Nance-Horan syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007161/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NHS](https://sugi.bio/atlas/gene/NHS/) |
| Protein change (HGVS p.) | p.Phe1007fs |
| Coding change (HGVS c.) | c.3021del |
| MANE Select transcript | [NM_001291867](https://www.ncbi.nlm.nih.gov/nuccore/NM_001291867) |
| dbSNP | [rs2519938991](https://www.ncbi.nlm.nih.gov/snp/rs2519938991/) |
| Variant type | Deletion |
| Location | chrX:17727125-17727125 (GRCh38) |
| ClinVar | [VCV1996935](https://www.ncbi.nlm.nih.gov/clinvar/variation/1996935/) |

**All HGVS expressions:** `NC_000023.10:g.17745247del`, `NC_000023.11:g.17727127del`, `NG_011553.2:g.356708del`, `NM_001136024.4:c.2490del`, `NM_001291867.2:c.3021del`, `NM_001291868.2:c.2427del`, `NM_198270.4:c.2958del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 2.156, GERP -1.97, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**NHS** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Nance-Horan syndrome** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 43.65, 4% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of NHS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

NHS participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-20 |

## Associated conditions {#conditions}

[Nance-Horan syndrome](https://sugi.bio/atlas/disease/nance-horan-syndrome/).

**Reported phenotype names (ClinVar):** Nance-Horan syndrome.

## Similar variants {#similar}

Related NHS variant pages (same residue, condition, or type): [NHS p.Ala1306fs](/variant/nhs-p-ala1306fs), [NHS p.Ser110_Ala116del](/variant/nhs-p-ser110-ala116del), [NHS p.Pro104_Ala115del](/variant/nhs-p-pro104-ala115del), [NHS p.Ala117fs](/variant/nhs-p-ala117fs), [NHS p.Arg17fs](/variant/nhs-p-arg17fs), [NHS p.Arg468fs](/variant/nhs-p-arg468fs), [NHS p.Asp488fs](/variant/nhs-p-asp488fs), [NHS p.Asp79fs](/variant/nhs-p-asp79fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1996935). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*