# NM_002485.5(NBN):c.1483_1484delinsA (p.Pro495fs)

https://sugi.bio/variant/nbn-p-pro495fs

## Summary

**NBN p.Pro495fs (c.1483_1484delinsA)** is classified **Pathogenic/Likely pathogenic** in NBN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-27). Ultra-rare (gnomAD MAF 6.704e-06); Associated with aplastic anemia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs764884516 · 7 submitters · 4 linked conditions · ultra-rare (gnomAD MAF 6.704e-06)

## For patients & families {#patients}

This is a change in the NBN gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to aplastic anemia.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 232 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0020234/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NBN](https://sugi.bio/atlas/gene/NBN/) |
| Protein change (HGVS p.) | p.Pro495fs |
| Coding change (HGVS c.) | c.1483_1484delinsA |
| MANE Select transcript | [NM_057091](https://www.ncbi.nlm.nih.gov/nuccore/NM_057091) (variant reported on NM_002485) |
| dbSNP | [rs764884516](https://www.ncbi.nlm.nih.gov/snp/rs764884516/) |
| Variant type | Indel |
| Location | chr8:89953605-89953606 (GRCh38) |
| ClinVar | [VCV186736](https://www.ncbi.nlm.nih.gov/clinvar/variation/186736/) |

**All HGVS expressions:** `LRG_158:g.36066_36067delinsA`, `NC_000008.10:g.90965833_90965834delinsT`, `NC_000008.11:g.89953605_89953606delinsT`, `NG_008860.1:g.36066_36067delinsA`, `NM_001024688.3:c.1237_1238delinsA`, `NM_002485.4:c.1483_1484delCCinsA`, `NM_002485.5:c.1483_1484delinsA`

## 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 8.556, GERP 1.79, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.00067%** — ultra-rare (gnomAD MAF 6.704e-06).

*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}


Curated gene–disease validity (ClinGen):

- **Nijmegen breakage syndrome** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.83, 47% of residues very-high.

**5 experimental structure(s)** (PDB): [2ASK](https://www.rcsb.org/structure/2ASK), [2GH0](https://www.rcsb.org/structure/2GH0), [2GYR](https://www.rcsb.org/structure/2GYR), [2GYZ](https://www.rcsb.org/structure/2GYZ), [6Q2S](https://www.rcsb.org/structure/6Q2S).

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

*Describes the biological roles of NBN (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:** NBN's established molecular role includes growth factor activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |

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

**Molecular function:** growth factor activity.

**Biological process:** glial cell-derived neurotrophic factor receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-27.

**Submitter consensus:** conflicting (5 Pathogenic, 2 Likely pathogenic).

**Submission history:** 7 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-06 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-14 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-01-02 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-15 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-27 |

## Associated conditions {#conditions}

[aplastic anemia](https://sugi.bio/atlas/disease/aplastic-anemia/), [acute lymphoblastic leukemia](https://sugi.bio/atlas/disease/acute-lymphoblastic-leukemia/), [Nijmegen breakage syndrome](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Aplastic anemia, Hereditary cancer-predisposing syndrome, not provided, Microcephaly, normal intelligence and immunodeficiency, Acute lymphoid leukemia, IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY, SEEMANOVA SYNDROME II, Immunodeficiency, microcephaly with normal intelligence, Ataxia telangiectasia variant V1, Nijmegen breakage syndrome.

## Similar variants {#similar}

Related NBN variant pages (same residue, condition, or type): [NBN p.Pro495Arg](/variant/nbn-p-pro495arg), [NBN p.Pro495Leu](/variant/nbn-p-pro495leu), [NBN p.Pro495Ser](/variant/nbn-p-pro495ser), [NBN p.Pro495Thr](/variant/nbn-p-pro495thr), [NBN p.Pro495Ala](/variant/nbn-p-pro495ala), [NBN c.585-1_585delinsC](/variant/nbn-c-585-minus-1-585delinsc), [NBN p.Glu179fs](/variant/nbn-p-glu179fs), [NBN p.Pro198fs](/variant/nbn-p-pro198fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 186736). 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.*