# NM_001063.4(TF):c.147del (p.Pro50fs)

https://sugi.bio/variant/tf-p-pro50fs

## Summary

**TF p.Pro50fs (c.147del)** is classified **Likely pathogenic** in TF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). Associated with atransferrinemia.

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

## For patients & families {#patients}

This is a change in the TF gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to atransferrinemia.

*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) | Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TF is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Congenital atransferrinemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Anemia — Very frequent (99-80%)
- Recurrent infections — Frequent (79-30%)
- Hypothyroidism — Occasional (29-5%)
- Arthritis — Occasional (29-5%)
- Abnormality of the cardiovascular system — Occasional (29-5%)
- Abnormality of the pancreas — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009595/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TF](https://sugi.bio/atlas/gene/TF/) |
| Protein change (HGVS p.) | p.Pro50fs |
| Coding change (HGVS c.) | c.147del |
| MANE Select transcript | [NM_001063](https://www.ncbi.nlm.nih.gov/nuccore/NM_001063) |
| Variant type | Deletion |
| Location | chr3:133748514-133748514 (GRCh38) |
| ClinVar | [VCV3588594](https://www.ncbi.nlm.nih.gov/clinvar/variation/3588594/) |

**All HGVS expressions:** `NC_000003.11:g.133467359del`, `NC_000003.12:g.133748515del`, `NG_013080.2:g.91518del`, `NG_013080.3:g.91519del`, `NM_001063.4:c.147del`, `NM_001354703.2:c.15del`, `NM_001354704.2:c.-166+2032del`

## 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 -1.032, GERP -2.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.834, pLI 1.0745e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 17**, 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}

**TF** population constraint: LOEUF 0.834, pLI 1.0745e-12, missense-Z 2.0561. *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):

- **atransferrinemia** — Moderate (AR)

## Protein context {#protein}

Residue **50** lies in the transferrin-like 1 domain.

AlphaFold model confidence (whole protein): pLDDT 93.39, 86% of residues very-high.

**69 experimental structure(s)** (PDB): [1A8E](https://www.rcsb.org/structure/1A8E), [1A8F](https://www.rcsb.org/structure/1A8F), [1B3E](https://www.rcsb.org/structure/1B3E), [1BP5](https://www.rcsb.org/structure/1BP5), [1BTJ](https://www.rcsb.org/structure/1BTJ), [1D3K](https://www.rcsb.org/structure/1D3K) — incl. mutant structure 1DTG.

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

*Describes the biological roles of TF (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:** TF's established molecular role includes ferrous iron binding. p.Pro50fs falls in the transferrin-like 1 domain.


### Pathways affected {#pathways}

TF participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Iron uptake and transport](https://reactome.org/content/detail/R-HSA-917937) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Transferrin endocytosis and recycling](https://reactome.org/content/detail/R-HSA-917977) | curated |

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

**Molecular function:** ferrous iron binding, enzyme binding, iron chaperone activity, transmembrane transporter binding, transferrin receptor binding.

**Biological process:** iron ion transport, intracellular iron ion homeostasis, cell surface receptor signaling pathway, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, positive regulation of receptor-mediated endocytosis, multicellular organismal-level iron ion homeostasis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-06-07 |

## Associated conditions {#conditions}

[atransferrinemia](https://sugi.bio/atlas/disease/atransferrinemia/).

**Reported phenotype names (ClinVar):** Atransferrinemia, Familial hypotransferrinemia.

## Similar variants {#similar}

Related TF variant pages (same residue, condition, or type): [TF p.Gly335_Tyr336insTer](/variant/tf-p-gly335-tyr336inster), [TF c.1623-63del](/variant/tf-c-1623-minus-63del), [TF c.-18C>T](/variant/tf-c-minus-18c-t), [TF p.Ala72Val](/variant/tf-p-ala72val), [TF p.Gln264Glu](/variant/tf-p-gln264glu), [TF p.Ile229Thr](/variant/tf-p-ile229thr), [TF p.Thr112Ala](/variant/tf-p-thr112ala), [TF p.Val451Ala](/variant/tf-p-val451ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3588594). 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.*