# NM_021930.6(RINT1):c.1207_1210del (p.Asp403fs)

https://sugi.bio/variant/rint1-p-asp403fs

## Summary

**RINT1 p.Asp403fs (c.1207_1210del)** is classified **Likely pathogenic** in RINT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). Associated with infantile liver failure syndrome 3.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the RINT1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to infantile liver failure syndrome 3.

*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 recessive |
| Age of onset (of this condition) | Infancy |
| Diagnostic panels | RINT1 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016483/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RINT1](https://sugi.bio/atlas/gene/RINT1/) |
| Protein change (HGVS p.) | p.Asp403fs |
| Coding change (HGVS c.) | c.1207_1210del |
| MANE Select transcript | [NM_021930](https://www.ncbi.nlm.nih.gov/nuccore/NM_021930) |
| Variant type | Deletion |
| Location | chr7:105550358-105550361 (GRCh38) |
| ClinVar | [VCV4526601](https://www.ncbi.nlm.nih.gov/clinvar/variation/4526601/) |

**All HGVS expressions:** `NC_000007.13:g.105190807_105190810del`, `NC_000007.14:g.105550360_105550363del`, `NG_051951.1:g.23280_23283del`, `NM_001346599.2:c.973_976del`, `NM_001346600.2:c.184_187del`, `NM_001346601.2:c.283_286del`, `NM_001346603.2:c.184_187del`, `NM_021930.6:c.1207_1210del`, `NM_021930.6:c.1207_1210delGATG`, `NR_144478.2:n.1322_1325del`

## 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 11.79, GERP 3.42, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.931, pLI 3.8414e-15. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 15**, 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.

*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}

**RINT1** population constraint: LOEUF 0.931, pLI 3.8414e-15, missense-Z 0.92023; ClinGen dosage — haploinsufficiency 0/3, 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):

- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **403** lies in the rint1/tip20 domain.

AlphaFold model confidence (whole protein): pLDDT 85.97, 63% of residues very-high.

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

*Describes the biological roles of RINT1 (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.*


### Pathways affected {#pathways}

RINT1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [COPI-dependent Golgi-to-ER retrograde traffic](https://reactome.org/content/detail/R-HSA-6811434) | other |

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

**Biological process:** mitotic G2 DNA damage checkpoint signaling, regulation of ER to Golgi vesicle-mediated transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-11.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-11 |

## Associated conditions {#conditions}

[infantile liver failure syndrome 3](https://sugi.bio/atlas/disease/infantile-liver-failure-syndrome-3/).

**Reported phenotype names (ClinVar):** Infantile liver failure syndrome 3.

## Similar variants {#similar}

Related RINT1 variant pages (same residue, condition, or type): [RINT1 p.Asp403Asn](/variant/rint1-p-asp403asn), [RINT1 p.Asp403Glu](/variant/rint1-p-asp403glu), [RINT1 p.Asp403Gly](/variant/rint1-p-asp403gly), [RINT1 p.Asp403His](/variant/rint1-p-asp403his), [RINT1 p.Asp403Tyr](/variant/rint1-p-asp403tyr), [RINT1 p.Asp403Val](/variant/rint1-p-asp403val), [RINT1 p.Val618_Lys619del](/variant/rint1-p-val618-lys619del), [RINT1 p.Asp403=](/variant/rint1-p-asp403).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 4526601). 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.*