# NM_005422.4(TECTA):c.12dup (p.Ser5fs)

https://sugi.bio/variant/tecta-p-ser5fs

## Summary

**TECTA p.Ser5fs (c.12dup)** is classified **Likely pathogenic** in TECTA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-02). No gnomAD frequency available for this variant; Associated with nonsyndromic genetic hearing loss.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2496881864 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TECTA gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to nonsyndromic genetic hearing loss.

*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, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TECTA is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Rare non-syndromic genetic deafness** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prelingual sensorineural hearing impairment — Frequent (79-30%)
- Progressive sensorineural hearing impairment — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Abnormal speech discrimination — Frequent (79-30%)
- Postlingual sensorineural hearing impairment — Frequent (79-30%)
- Profound sensorineural hearing impairment — Frequent (79-30%)
- Conductive hearing impairment — Occasional (29-5%)
- High-frequency hearing impairment — Occasional (29-5%)

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

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TECTA](https://sugi.bio/atlas/gene/TECTA/) |
| Protein change (HGVS p.) | p.Ser5fs |
| Coding change (HGVS c.) | c.12dup |
| MANE Select transcript | [NM_005422](https://www.ncbi.nlm.nih.gov/nuccore/NM_005422) |
| dbSNP | [rs2496881864](https://www.ncbi.nlm.nih.gov/snp/rs2496881864/) |
| Variant type | Duplication |
| Location | chr11:121102676-121102677 (GRCh38) |
| ClinVar | [VCV3075938](https://www.ncbi.nlm.nih.gov/clinvar/variation/3075938/) |

**All HGVS expressions:** `NC_000011.10:g.121102677dup`, `NC_000011.9:g.120973386dup`, `NG_011633.1:g.5012dup`, `NM_001378761.1:c.969dup`, `NM_005422.4:c.12dup`

## 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 7.708, GERP 1.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.661, pLI 1.9954e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 24**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**TECTA** population constraint: LOEUF 0.661, pLI 1.9954e-20, missense-Z 2.4637. *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):

- **nonsyndromic genetic hearing loss** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.64, 19% of residues very-high.

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

*Describes the biological roles of TECTA (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Post-translational modification: synthesis of GPI-anchored proteins](https://reactome.org/content/detail/R-HSA-163125) | curated |

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-02-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-02 |

## Associated conditions {#conditions}

[nonsyndromic genetic hearing loss](https://sugi.bio/atlas/disease/nonsyndromic-genetic-hearing-loss/).

**Reported phenotype names (ClinVar):** Nonsyndromic genetic hearing loss, Nonsyndromic hearing loss and deafness, Non-syndromic genetic deafness, Nonsyndromic genetic deafness.

## Similar variants {#similar}

Related TECTA variant pages (same residue, condition, or type): [TECTA p.Arg371Gly](/variant/tecta-p-arg371gly), [TECTA p.Gly1335Glu](/variant/tecta-p-gly1335glu), [TECTA p.Met1811del](/variant/tecta-p-met1811del), [TECTA p.Ser373fs](/variant/tecta-p-ser373fs), [TECTA p.Gly579fs](/variant/tecta-p-gly579fs).

### 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 3075938). 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.*