# NM_177438.3(DICER1):c.4984del (p.Ile1663fs)

https://sugi.bio/variant/dicer1-p-ile1663fs

## Summary

**DICER1 p.Ile1663fs (c.4984del)** is classified **Pathogenic** in DICER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-08). No gnomAD frequency available for this variant; Associated with DICER1-related tumor predisposition.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1131691196 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DICER1 gene that is considered disease-causing, submitted by 2 submitters, and is linked to DICER1-related tumor predisposition.

*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) | Adolescent, Adult, Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DICER1 is a diagnostic-grade gene on 9 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010734/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DICER1](https://sugi.bio/atlas/gene/DICER1/) |
| Protein change (HGVS p.) | p.Ile1663fs |
| Coding change (HGVS c.) | c.4984del |
| MANE Select transcript | [NM_177438](https://www.ncbi.nlm.nih.gov/nuccore/NM_177438) |
| dbSNP | [rs1131691196](https://www.ncbi.nlm.nih.gov/snp/rs1131691196/) |
| Variant type | Deletion |
| Location | chr14:95095936-95095936 (GRCh38) |
| ClinVar | [VCV429121](https://www.ncbi.nlm.nih.gov/clinvar/variation/429121/) |

**All HGVS expressions:** `LRG_492:g.66487del`, `LRG_492t1:c.4984del`, `NC_000014.8:g.95562274del`, `NC_000014.9:g.95095937del`, `NG_016311.1:g.66487del`, `NM_001195573.1:c.4984del`, `NM_001271282.3:c.4984del`, `NM_001291628.2:c.4984del`, `NM_030621.4:c.4984del`, `NM_177438.2:c.4984delC`, `NM_177438.3:c.4984del`

## 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 11.258, GERP 1.74, 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 0.275, 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 23 of 27**, 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}

**DICER1** population constraint: LOEUF 0.275, pLI 1, missense-Z 6.1513; 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):

- **DICER1-related tumor predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **1663** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 67.89, 17% of residues very-high.

**21 experimental structure(s)** (PDB): [21CB](https://www.rcsb.org/structure/21CB), [21CN](https://www.rcsb.org/structure/21CN), [21CQ](https://www.rcsb.org/structure/21CQ), [2EB1](https://www.rcsb.org/structure/2EB1), [4NGB](https://www.rcsb.org/structure/4NGB), [4NGC](https://www.rcsb.org/structure/4NGC).

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

*Describes the biological roles of DICER1 (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:** DICER1's established molecular role includes double-stranded RNA binding.


### Pathways affected {#pathways}

DICER1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MicroRNA (miRNA) biogenesis](https://reactome.org/content/detail/R-HSA-203927) | curated |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | curated |
| [Small interfering RNA (siRNA) biogenesis](https://reactome.org/content/detail/R-HSA-426486) | curated |
| [M-decay: degradation of maternal mRNAs by maternally stored factors](https://reactome.org/content/detail/R-HSA-9820841) | electronic |
| [tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis](https://reactome.org/content/detail/R-HSA-9708296) | electronic |

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

**Molecular function:** double-stranded RNA binding, RNA endonuclease activity, ribonuclease III activity, protein domain specific binding, siRNA binding, pre-miRNA binding.

**Biological process:** negative regulation of gene expression, negative regulation of tumor necrosis factor-mediated signaling pathway, siRNA processing, pre-miRNA processing, negative regulation of tumor necrosis factor production, miRNA processing.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-08.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-16 |

## Associated conditions {#conditions}

[DICER1-related tumor predisposition](https://sugi.bio/atlas/disease/dicer1-related-tumor-predisposition/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** DICER1-related tumor predisposition, Hereditary cancer-predisposing syndrome, DICER1-related pleuropulmonary blastoma cancer predisposition syndrome, DICER1 syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related DICER1 variant pages (same residue, condition, or type): [DICER1 p.Ile1663Met](/variant/dicer1-p-ile1663met), [DICER1 p.Ile1663Thr](/variant/dicer1-p-ile1663thr), [DICER1 p.Ile1663Val](/variant/dicer1-p-ile1663val), [DICER1 p.Ile1663Leu](/variant/dicer1-p-ile1663leu), [DICER1 p.Ile1663=](/variant/dicer1-p-ile1663), [DICER1 p.Arg293fs](/variant/dicer1-p-arg293fs), [DICER1 p.Glu292fs](/variant/dicer1-p-glu292fs), [DICER1 p.Ile627fs](/variant/dicer1-p-ile627fs).

### 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 429121). 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.*