# NM_001256317.3(TMPRSS3):c.1335_1339dup (p.Met447fs)

https://sugi.bio/variant/tmprss3-p-met447fs

## Summary

**TMPRSS3 p.Met447fs (c.1335_1339dup)** is classified **Pathogenic** in TMPRSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-18). Very rare (popmax 0.000678%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1351236437 · 1 submitter · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the TMPRSS3 gene that is reported as disease-causing, but on limited review, 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 | [TMPRSS3](https://sugi.bio/atlas/gene/TMPRSS3/) |
| Protein change (HGVS p.) | p.Met447fs |
| Coding change (HGVS c.) | c.1335_1339dup |
| MANE Select transcript | [NM_001256317](https://www.ncbi.nlm.nih.gov/nuccore/NM_001256317) |
| dbSNP | [rs1351236437](https://www.ncbi.nlm.nih.gov/snp/rs1351236437/) |
| Variant type | Duplication |
| Location | chr21:42375720-42375721 (GRCh38) |
| ClinVar | [VCV1909242](https://www.ncbi.nlm.nih.gov/clinvar/variation/1909242/) |

**All HGVS expressions:** `NC_000021.8:g.43795832_43795836dup`, `NC_000021.9:g.42375723_42375727dup`, `NG_011629.2:g.25367_25371dup`, `NM_001256317.3:c.1335_1339dup`, `NM_024022.4:c.1338_1342dup`, `NM_032404.3:c.957_961dup`

## 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 10.929, GERP 1.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.106, pLI 2.1224e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (12 of 13, 4 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 34.0**. 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 **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,180,006 in the highest group · 8/1,613,552 alleles overall — very rare (popmax 0.000678%, nfe).

*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}

**TMPRSS3** population constraint: LOEUF 1.106, pLI 2.1224e-16, missense-Z 0.23772; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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)

## Protein context {#protein}

Residue **447** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 87.09, 71% of residues very-high.

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

*Describes the biological roles of TMPRSS3 (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:** TMPRSS3's established molecular role includes sodium channel regulator activity. p.Met447fs falls in the peptidase s1 domain.


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

**Molecular function:** sodium channel regulator activity.

**Biological process:** intracellular sodium ion homeostasis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-18.

**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 | 2023-10-18 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **447** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TMPRSS3 p.Met447Thr](/variant/tmprss3-p-met447thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TMPRSS3 variant pages (same residue, condition, or type): [TMPRSS3 p.Met447Thr](/variant/tmprss3-p-met447thr), [TMPRSS3 p.Cys194fs](/variant/tmprss3-p-cys194fs), [TMPRSS3 c.617-3_617-2dup](/variant/tmprss3-c-617-minus-3-617-minus-2dup), [TMPRSS3 p.Pro403fs](/variant/tmprss3-p-pro403fs), [TMPRSS3 p.Pro50fs](/variant/tmprss3-p-pro50fs), [TMPRSS3 p.Ser14fs](/variant/tmprss3-p-ser14fs), [TMPRSS3 c.573-157_573-156dup](/variant/tmprss3-c-573-minus-157-573-minus-156dup), [TMPRSS3 c.573-157dup](/variant/tmprss3-c-573-minus-157dup).

### 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 1909242). 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.*