# NM_001114753.3(ENG):c.991+2T>C

https://sugi.bio/variant/eng-c-991-plus-2t-c

## Summary

**ENG c.991+2T>C** is classified **Pathogenic** in ENG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-21). Absent from gnomAD v4.1; Associated with telangiectasia, hereditary hemorrhagic, type 1.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1564455554 · 4 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ENG gene that is considered disease-causing, submitted by 4 submitters, and is linked to telangiectasia, hereditary hemorrhagic, type 1.

*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) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ENG is a diagnostic-grade gene on 7 Genomics England panels |

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

- Lip telangiectasia — Very frequent (99-80%)
- Tongue telangiectasia — Very frequent (99-80%)
- Epistaxis — Very frequent (99-80%)
- Nasal mucosa telangiectasia — Very frequent (99-80%)
- Telangiectasia — Very frequent (99-80%)
- Spontaneous, recurrent epistaxis — Very frequent (99-80%)
- Mucosal telangiectasiae — Very frequent (99-80%)
- Telangiectasia of the skin — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024627/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ENG](https://sugi.bio/atlas/gene/ENG/) |
| Coding change (HGVS c.) | c.991+2T>C |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs1564455554](https://www.ncbi.nlm.nih.gov/snp/rs1564455554/) |
| Variant type | single nucleotide variant |
| Location | chr9:127824798-127824798 (GRCh38) |
| ClinVar | [VCV575140](https://www.ncbi.nlm.nih.gov/clinvar/variation/575140/) |

**All HGVS expressions:** `LRG_589:g.34971T>C`, `LRG_589t1:c.991+2T>C`, `NC_000009.11:g.130587077A>G`, `NC_000009.12:g.127824798A>G`, `NG_009551.1:g.34971T>C`, `NM_000118.4:c.991+2T>C`, `NM_001114753.2:c.991+2T>C`, `NM_001114753.3:c.991+2T>C`, `NM_001278138.2:c.445+2T>C`, `NM_001406715.1:c.991+2T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.97) — consistent with the pathogenic call
- Conservation: phyloP 10.997, GERP 0.522, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **canonical splice-site (±1/±2)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.374, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 24.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **canonical splice dinucleotide (donor +2)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.97**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 2 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.80** (loss), gain 0.01 / loss 0.80. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ENG** population constraint: LOEUF 0.374, pLI 1, missense-Z 1.285; ClinGen dosage — haploinsufficiency 3, 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):

- **juvenile polyposis syndrome** — Limited (AD)
- **telangiectasia, hereditary hemorrhagic, type 1** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 80.84, 40% of residues very-high.

**3 experimental structure(s)** (PDB): [5HZV](https://www.rcsb.org/structure/5HZV), [5HZW](https://www.rcsb.org/structure/5HZW), [5I04](https://www.rcsb.org/structure/5I04).

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

*Describes the biological roles of ENG (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:** ENG's established molecular role includes type II transforming growth factor beta receptor binding.


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

**Molecular function:** type II transforming growth factor beta receptor binding, galactose binding, glycosaminoglycan binding, coreceptor activity, signaling receptor activator activity, type I transforming growth factor beta receptor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, vasculogenesis, response to hypoxia, negative regulation of endothelial cell proliferation, positive regulation of systemic arterial blood pressure, regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-21.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-18 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-03 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-21 |

## Associated conditions {#conditions}

[telangiectasia, hereditary hemorrhagic, type 1](https://sugi.bio/atlas/disease/telangiectasia-hereditary-hemorrhagic-type-1/), [hereditary hemorrhagic telangiectasia](https://sugi.bio/atlas/disease/hereditary-hemorrhagic-telangiectasia/).

**Reported phenotype names (ClinVar):** Telangiectasia, hereditary hemorrhagic, type 1, Hereditary hemorrhagic telangiectasia, not provided, none provided, Osler Weber Rendu syndrome type 1, ENG-Related Hereditary Hemorrhagic Telangiectasia, ORW DISEASE, Osler Weber Rendu syndrome, OSLER-RENDU-WEBER DISEASE, Osler hemorrhagic telangiectasia syndrome.

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Arg529His](/variant/eng-p-arg529his), [ENG p.Asn423Ser](/variant/eng-p-asn423ser), [ENG p.Cys382Tyr](/variant/eng-p-cys382tyr), [ENG p.Cys549Gly](/variant/eng-p-cys549gly), [ENG p.Gly331Ser](/variant/eng-p-gly331ser), [ENG p.Gly603Arg](/variant/eng-p-gly603arg), [ENG p.Leu221Pro](/variant/eng-p-leu221pro), [ENG p.Leu506His](/variant/eng-p-leu506his).

### 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 575140). 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.*