# NM_004593.3(TRA2B):c.-11_12del (p.Met1fs)

https://sugi.bio/variant/tra2b-p-met1fs

## Summary

**TRA2B p.Met1fs (c.-11_12del)** is classified **Uncertain significance** in TRA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the TRA2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TRA2B](https://sugi.bio/atlas/gene/TRA2B/) |
| Protein change (HGVS p.) | p.Met1fs |
| Coding change (HGVS c.) | c.-11_12del |
| MANE Select transcript | [NM_004593](https://www.ncbi.nlm.nih.gov/nuccore/NM_004593) |
| Variant type | Deletion |
| Location | chr3:185937849-185937871 (GRCh38) |
| ClinVar | [VCV3359950](https://www.ncbi.nlm.nih.gov/clinvar/variation/3359950/) |

**All HGVS expressions:** `NC_000003.11:g.185655645_185655667del`, `NC_000003.12:g.185937857_185937879del`, `NG_029862.1:g.5266_5288del`, `NG_101337.2:g.722_744del`, `NM_001243879.2:c.-177_-155del`, `NM_004593.3:c.-11_12del`

## 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 7.44, GERP 2.15, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.528, pLI 0.95587), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 9**, 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}

**TRA2B** population constraint: LOEUF 0.528, pLI 0.95587, missense-Z 4.2143. *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):

- **syndromic complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **1** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 57.18, 18% of residues very-high.

**4 experimental structure(s)** (PDB): [2CQC](https://www.rcsb.org/structure/2CQC), [2KXN](https://www.rcsb.org/structure/2KXN), [2RRA](https://www.rcsb.org/structure/2RRA), [2RRB](https://www.rcsb.org/structure/2RRB).

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

*Describes the biological roles of TRA2B (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:** TRA2B's established molecular role includes RNA binding. p.Met1fs falls in the disordered region.


### Pathways affected {#pathways}

TRA2B participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Processing of Capped Intron-Containing Pre-mRNA](https://reactome.org/content/detail/R-HSA-72203) | other |
| [RHOBTB1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013422) | other |
| [RHOBTB2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013418) | other |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | other |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | other |

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

**Molecular function:** RNA binding, mRNA binding, protein domain specific binding, pre-mRNA binding, identical protein binding.

**Biological process:** regulation of alternative mRNA splicing, via spliceosome, mRNA splicing, via spliceosome, regulation of RNA splicing, positive regulation of mRNA splicing, via spliceosome, cellular response to glucose stimulus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-14.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-14 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Same-residue context {#hotspot}

Residue **1** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [TRA2B p.Met1Arg](/variant/tra2b-p-met1arg), [TRA2B p.Met1del](/variant/tra2b-p-met1del), [TRA2B p.Met1Val](/variant/tra2b-p-met1val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TRA2B variant pages (same residue, condition, or type): [TRA2B p.Met1del](/variant/tra2b-p-met1del), [TRA2B p.Met1Arg](/variant/tra2b-p-met1arg), [TRA2B p.Met1Val](/variant/tra2b-p-met1val), [TRA2B p.Arg15fs](/variant/tra2b-p-arg15fs), [TRA2B p.His94fs](/variant/tra2b-p-his94fs), [TRA2B c.170+1del](/variant/tra2b-c-170-plus-1del).

### 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 3359950). 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.*