# NM_012179.4(FBXO7):c.417+141del

https://sugi.bio/variant/fbxo7-c-417-plus-141del

## Summary

**FBXO7 c.417+141del** is classified **Benign** in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-02). Common (popmax 50.3%, eas) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Single submitter · rsID rs5845002 · 1 submitter · common (popmax 50.3%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the FBXO7 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FBXO7](https://sugi.bio/atlas/gene/FBXO7/) |
| Coding change (HGVS c.) | c.417+141del |
| MANE Select transcript | [NM_012179](https://www.ncbi.nlm.nih.gov/nuccore/NM_012179) |
| dbSNP | [rs5845002](https://www.ncbi.nlm.nih.gov/snp/rs5845002/) |
| Variant type | Deletion |
| Location | chr22:32479402-32479402 (GRCh38) |
| ClinVar | [VCV1231788](https://www.ncbi.nlm.nih.gov/clinvar/variation/1231788/) |

**All HGVS expressions:** `NC_000022.10:g.32875403del`, `NC_000022.11:g.32479416del`, `NG_016001.2:g.9697del`, `NM_001033024.2:c.180+141del`, `NM_001257990.2:c.75+141del`, `NM_012179.4:c.417+141del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 50.3%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -3.202, GERP -0.302 — fast-evolving / accelerated position
- CADD: **PHRED 0.02**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **deep intronic (+141 nt into the intron)**.
- Non-coding constraint (Gnocchi): **Z 0.64**, o/e 0.94 (1 kb window 32,479,000–32,480,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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 (gnomAD v4.1): grpmax **50.3%** (eas) · FAF95 49.6% · FAF99 49.3% · 13,242/26,326 in the highest group · 206,000/566,958 alleles overall — common (popmax 50.3%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 50.3% | 2 |
| African / African-American | 44.8% | 2 |
| Admixed American | 44.3% | 2 |
| South Asian | 39.7% | 3 |
| Finnish (not grpmax-eligible) | 39.4% | 3 |
| Remaining individuals (not grpmax-eligible) | 36.1% | 3 |
| Middle Eastern | 36.1% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 36% | 3 |
| European (non-Finnish) | 33.1% | 3 |
| Amish (not grpmax-eligible) | 31.8% | 3 |

*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}

**FBXO7** population constraint: LOEUF 0.955, pLI 2.9822e-07, missense-Z -0.0088092; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 67.13, 13% of residues very-high.

**2 experimental structure(s)** (PDB): [4L9C](https://www.rcsb.org/structure/4L9C), [4L9H](https://www.rcsb.org/structure/4L9H).

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

*Describes the biological roles of FBXO7 (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:** FBXO7's established molecular role includes protein kinase binding.


### Pathways affected {#pathways}

FBXO7 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |

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

**Molecular function:** protein kinase binding, ubiquitin protein ligase binding, ubiquitin binding, protein heterodimerization activity, ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** autophagy of mitochondrion, ubiquitin-dependent protein catabolic process, obsolete protein targeting to mitochondrion, regulation of neuron projection development, protein ubiquitination, SCF-dependent proteasomal ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-01-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2021-01-02 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related FBXO7 variant pages (same residue, condition, or type): [FBXO7 p.Pro484fs](/variant/fbxo7-p-pro484fs), [FBXO7 p.Arg513fs](/variant/fbxo7-p-arg513fs), [FBXO7 c.1183-2_1183-1del](/variant/fbxo7-c-1183-minus-2-1183-minus-1del), [FBXO7 p.Asn51fs](/variant/fbxo7-p-asn51fs), [FBXO7 p.Asp348fs](/variant/fbxo7-p-asp348fs), [FBXO7 p.Cys192fs](/variant/fbxo7-p-cys192fs), [FBXO7 p.Gly126fs](/variant/fbxo7-p-gly126fs), [FBXO7 p.Leu106fs](/variant/fbxo7-p-leu106fs).

### 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 1231788). 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.*