# NM_001386135.1(AFF3):c.1063_1064del (p.Pro356fs)

https://sugi.bio/variant/aff3-p-pro356fs

## Summary

**AFF3 p.Pro356fs (c.1063_1064del)** is classified **Uncertain significance** in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the AFF3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [AFF3](https://sugi.bio/atlas/gene/AFF3/) |
| Protein change (HGVS p.) | p.Pro356fs |
| Coding change (HGVS c.) | c.1063_1064del |
| MANE Select transcript | [NM_001386135](https://www.ncbi.nlm.nih.gov/nuccore/NM_001386135) |
| Variant type | Microsatellite |
| Location | chr2:99727104-99727105 (GRCh38) |
| ClinVar | [VCV3900204](https://www.ncbi.nlm.nih.gov/clinvar/variation/3900204/) |

**All HGVS expressions:** `NC_000002.11:g.100343566CT[2]`, `NC_000002.12:g.99727104CT[2]`, `NG_052835.1:g.420475AG[2]`, `NM_001025108.2:c.1138_1139del`, `NM_001386135.1:c.1063_1064del`, `NM_002285.3:c.1063_1064del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 2.993, GERP -0.287, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.318, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 25**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**AFF3** population constraint: LOEUF 0.318, pLI 1, missense-Z 2.2654. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **356** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 52.20, 15% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-11-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-26 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related AFF3 variant pages (same residue, condition, or type): [AFF3 c.-64-274CGG[(797_850](/variant/aff3-c-minus-64-minus-274cgg-797-850), [AFF3 p.Ala611_Asp612insAlaAla](/variant/aff3-p-ala611-asp612insalaala), [AFF3 p.Asn937del](/variant/aff3-p-asn937del), [AFF3 p.Glu687del](/variant/aff3-p-glu687del), [AFF3 p.Pro104_Val105insGlnThrPro](/variant/aff3-p-pro104-val105insglnthrpro).

### 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 3900204). 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.*