# NM_005422.4(TECTA):c.1115dup (p.Ser373fs)

https://sugi.bio/variant/tecta-p-ser373fs

## Summary

**TECTA p.Ser373fs (c.1115dup)** is classified **Pathogenic/Likely pathogenic** in TECTA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). Very rare (popmax 0.00475%, nfe); Associated with TECTA-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1380941851 · 2 submitters · 2 linked conditions · very rare (popmax 0.00475%, nfe)

## For patients & families {#patients}

This is a change in the TECTA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to TECTA-related disorder.

*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 | [TECTA](https://sugi.bio/atlas/gene/TECTA/) |
| Protein change (HGVS p.) | p.Ser373fs |
| Coding change (HGVS c.) | c.1115dup |
| MANE Select transcript | [NM_005422](https://www.ncbi.nlm.nih.gov/nuccore/NM_005422) |
| dbSNP | [rs1380941851](https://www.ncbi.nlm.nih.gov/snp/rs1380941851/) |
| Variant type | Duplication |
| Location | chr11:121118628-121118629 (GRCh38) |
| ClinVar | [VCV1708127](https://www.ncbi.nlm.nih.gov/clinvar/variation/1708127/) |

**All HGVS expressions:** `NC_000011.10:g.121118630dup`, `NC_000011.9:g.120989339dup`, `NG_011633.1:g.20965dup`, `NM_001378761.1:c.2072dup`, `NM_005422.4:c.1115dup`, `NM_005422.4:c.1115dupG`

## 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 -0.612, GERP -3.56, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 7 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 32.0**. 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.*
- 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 (gnomAD v4.1): grpmax **0.00475%** (nfe) · FAF95 0.00375% · FAF99 0.00337% · 56/1,180,034 in the highest group · 58/1,613,938 alleles overall — very rare (popmax 0.00475%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00475% | 21,072 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |

*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}

Residue **373** lies in the vwfd 1 domain.

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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-05-30.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-12 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-30 |

## Associated conditions {#conditions}

[TECTA-related disorder](https://sugi.bio/atlas/disease/tecta-related-disorder/), [autosomal dominant nonsyndromic hearing loss 12](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-12/).

**Reported phenotype names (ClinVar):** TECTA-related disorder, Autosomal dominant nonsyndromic hearing loss 12, TECTA-related condition, DEAFNESS, AUTOSOMAL DOMINANT 8.

## Similar variants {#similar}

Related TECTA variant pages (same residue, condition, or type): [TECTA p.Gly579fs](/variant/tecta-p-gly579fs), [TECTA p.Arg371Gly](/variant/tecta-p-arg371gly), [TECTA c.4690-1G>A](/variant/tecta-c-4690-minus-1g-a), [TECTA p.Ala567Thr](/variant/tecta-p-ala567thr), [TECTA p.Arg284Cys](/variant/tecta-p-arg284cys), [TECTA p.Arg474Cys](/variant/tecta-p-arg474cys), [TECTA p.Cys1072=](/variant/tecta-p-cys1072), [TECTA p.Cys1402Ser](/variant/tecta-p-cys1402ser).

### 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 1708127). 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.*