# NM_001042492.3(NF1):c.4989_4992del (p.Phe1663fs)

https://sugi.bio/variant/nf1-p-phe1663fs

## Summary

**NF1 p.Phe1663fs (c.4989_4992del)** is classified **Pathogenic** in NF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-21). No gnomAD frequency available for this variant; Associated with neurofibromatosis type 1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2508695819 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the NF1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to neurofibromatosis type 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-5 / 10 000 (United Kingdom) |
| Clinical trials | 176 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NF1 is a diagnostic-grade gene on 28 Genomics England panels |

**Commonly reported features of Neurofibromatosis type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Delayed puberty — Very frequent (99-80%)
- Melanocytic nevus — Very frequent (99-80%)
- Multiple lipomas — Very frequent (99-80%)
- Intellectual disability, mild — Very frequent (99-80%)
- Specific learning disability — Very frequent (99-80%)
- Subcutaneous nodule — Very frequent (99-80%)
- Meningioma — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NF1](https://sugi.bio/atlas/gene/NF1/) |
| Protein change (HGVS p.) | p.Phe1663fs |
| Coding change (HGVS c.) | c.4989_4992del |
| MANE Select transcript | [NM_001042492](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042492) |
| dbSNP | [rs2508695819](https://www.ncbi.nlm.nih.gov/snp/rs2508695819/) |
| Variant type | Deletion |
| Location | chr17:31325970-31325973 (GRCh38) |
| ClinVar | [VCV2007801](https://www.ncbi.nlm.nih.gov/clinvar/variation/2007801/) |

**All HGVS expressions:** `LRG_214:g.235997_236000del`, `LRG_214t1:c.4926_4929del`, `LRG_214t2:c.4989_4992del`, `NC_000017.10:g.29652991_29652994del`, `NC_000017.11:g.31325973_31325976del`, `NG_009018.1:g.235997_236000del`, `NM_000267.4:c.4926_4929delTGTT`, `NM_001042492.3:c.4989_4992del`

## 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 11.883, GERP 1.56, 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 (constraint LOEUF 0.449, pLI 0.99946), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 37 of 58**, 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}

**NF1** population constraint: LOEUF 0.449, pLI 0.99946, missense-Z 8.4243; 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):

- **neurofibromatosis type 1** — Definitive (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **1663** lies in a turn; the cral-trio domain; the 'lipid binding' region.

**26 experimental structure(s)** (PDB): [1NF1](https://www.rcsb.org/structure/1NF1), [2D4Q](https://www.rcsb.org/structure/2D4Q), [2E2X](https://www.rcsb.org/structure/2E2X), [3P7Z](https://www.rcsb.org/structure/3P7Z), [3PEG](https://www.rcsb.org/structure/3PEG), [3PG7](https://www.rcsb.org/structure/3PG7) — incl. mutant structure 3PG7.

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

*Describes the biological roles of NF1 (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.*

**How this variant is thought to act:** NF1's established molecular role includes GTPase activator activity. p.Phe1663fs falls in the cral-trio domain. In Reactome, NF1 is annotated in disease pathway(s) including **RAS signaling downstream of NF1 loss-of-function variants**.

**Disease mechanism (Reactome):** NF1 loss or alteration is curated in [RAS signaling downstream of NF1 loss-of-function variants](https://reactome.org/content/detail/R-HSA-6802953).

### Pathways affected {#pathways}

NF1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [RAS signaling downstream of NF1 loss-of-function variants](https://reactome.org/content/detail/R-HSA-6802953) | curated |
| [Regulation of RAS by GAPs](https://reactome.org/content/detail/R-HSA-5658442) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activator activity, phosphatidylethanolamine binding, phosphatidylcholine binding.

**Biological process:** negative regulation of endothelial cell proliferation, negative regulation of cell migration, negative regulation of MAPK cascade, regulation of blood vessel endothelial cell migration, positive regulation of GTPase activity, regulation of angiogenesis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-21.

**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 | 2022-08-21 |

## Associated conditions {#conditions}

[neurofibromatosis type 1](https://sugi.bio/atlas/disease/neurofibromatosis-type-1/).

**Reported phenotype names (ClinVar):** Neurofibromatosis, type 1, Neurofibromatosis, type I, Peripheral type neurofibromatosis, VON RECKLINGHAUSEN DISEASE, NEUROFIBROMATOSIS, TYPE I, SOMATIC.

## Similar variants {#similar}

Related NF1 variant pages (same residue, condition, or type): [NF1 c.1183_1185+2del](/variant/nf1-c-1183-1185-plus-2del), [NF1 c.1392+2del](/variant/nf1-c-1392-plus-2del), [NF1 c.1527+1del](/variant/nf1-c-1527-plus-1del), [NF1 c.1527+4_1527+7del](/variant/nf1-c-1527-plus-4-1527-plus-7del), [NF1 c.1845+1_1845+5del](/variant/nf1-c-1845-plus-1-1845-plus-5del), [NF1 c.2002-2_2002-1del](/variant/nf1-c-2002-minus-2-2002-minus-1del), [NF1 c.204+3_204+6del](/variant/nf1-c-204-plus-3-204-plus-6del), [NF1 c.2252delG](/variant/nf1-c-2252delg).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2007801). 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.*