# NM_198253.3(TERT):c.2924_2925del (p.Phe975fs)

https://sugi.bio/variant/tert-p-phe975fs

## Summary

**TERT p.Phe975fs (c.2924_2925del)** is classified **Pathogenic** in TERT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). No gnomAD frequency available for this variant; Associated with idiopathic pulmonary fibrosis.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1579551402 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TERT gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to idiopathic pulmonary fibrosis.

*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) | Multigenic/multifactorial |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-5 / 10 000 (Worldwide) |
| Clinical trials | 537 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TERT is a diagnostic-grade gene on 16 Genomics England panels |

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

- Abnormal pulmonary interstitial morphology — Very frequent (99-80%)
- Acrocyanosis — Frequent (79-30%)
- Gastroesophageal reflux — Frequent (79-30%)
- Bronchiectasis — Frequent (79-30%)
- Pulmonary fibrosis — Frequent (79-30%)
- Exertional dyspnea — Frequent (79-30%)
- Fatigue — Frequent (79-30%)
- Cough — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0028067/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TERT](https://sugi.bio/atlas/gene/TERT/) |
| Protein change (HGVS p.) | p.Phe975fs |
| Coding change (HGVS c.) | c.2924_2925del |
| MANE Select transcript | [NM_198253](https://www.ncbi.nlm.nih.gov/nuccore/NM_198253) |
| dbSNP | [rs1579551402](https://www.ncbi.nlm.nih.gov/snp/rs1579551402/) |
| Variant type | Deletion |
| Location | chr5:1260519-1260520 (GRCh38) |
| ClinVar | [VCV2926044](https://www.ncbi.nlm.nih.gov/clinvar/variation/2926044/) |

**All HGVS expressions:** `LRG_343:g.39528_39529del`, `LRG_343t1:c.2923_2924del`, `NC_000005.10:g.1260520_1260521del`, `NC_000005.9:g.1260635_1260636del`, `NG_009265.1:g.39528_39529del`, `NM_001193376.3:c.2735_2736del`, `NM_003219.1:c.2923_2924delTT`, `NM_198253.3:c.2924_2925del`, `NR_149162.3:n.2632_2633del`, `NR_149163.3:n.2596_2597del`

## 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 0.127, GERP -1.67 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.593, pLI 0.0019285. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 16**, 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}

**TERT** population constraint: LOEUF 0.593, pLI 0.0019285, missense-Z 3.0616; ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *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):

- **dyskeratosis congenita, autosomal dominant 2** — Definitive (SD)

## Protein context {#protein}

Residue **975** lies in the 'cte' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.98, 60% of residues very-high.

**32 experimental structure(s)** (PDB): [2BCK](https://www.rcsb.org/structure/2BCK), [4B18](https://www.rcsb.org/structure/4B18), [4MNQ](https://www.rcsb.org/structure/4MNQ), [5MEN](https://www.rcsb.org/structure/5MEN), [5MEO](https://www.rcsb.org/structure/5MEO), [5MEP](https://www.rcsb.org/structure/5MEP).

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

*Describes the biological roles of TERT (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:** TERT's established molecular role includes tRNA binding. p.Phe975fs falls in the cte region.


### Pathways affected {#pathways}

TERT participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence](https://reactome.org/content/detail/R-HSA-9825895) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |

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

**Molecular function:** tRNA binding, transcription coactivator binding, DNA binding, telomerase activity, RNA binding, RNA-directed DNA polymerase activity.

**Biological process:** RNA-templated transcription, RNA-templated DNA biosynthetic process, protein import into nucleus, telomere maintenance via telomerase, mitochondrion organization, DNA strand elongation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-16 |

## Associated conditions {#conditions}

[idiopathic pulmonary fibrosis](https://sugi.bio/atlas/disease/idiopathic-pulmonary-fibrosis/), [dyskeratosis congenita, autosomal dominant 2](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-dominant-2/).

**Reported phenotype names (ClinVar):** Idiopathic Pulmonary Fibrosis, Dyskeratosis congenita, autosomal dominant 2, Idiopathic fibrosing alveolitis, chronic form, idiopathic fibrosing alveolitis.

## Similar variants {#similar}

Related TERT variant pages (same residue, condition, or type): [TERT p.Phe975Leu](/variant/tert-p-phe975leu), [TERT p.Phe975Val](/variant/tert-p-phe975val), [TERT p.Arg821fs](/variant/tert-p-arg821fs), [TERT p.Leu392fs](/variant/tert-p-leu392fs), [TERT p.Pro308fs](/variant/tert-p-pro308fs), [TERT p.Tyr333fs](/variant/tert-p-tyr333fs), [TERT c.2382+235_2453del](/variant/tert-c-2382-plus-235-2453del), [TERT p.Ala357fs](/variant/tert-p-ala357fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 2926044). 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.*