# NM_152468.5(TMC8):c.423del (p.Asp142fs)

https://sugi.bio/variant/tmc8-p-asp142fs

## Summary

**TMC8 p.Asp142fs (c.423del)** is classified **Pathogenic** in TMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). Very rare (popmax 0.00446%, eas); Associated with epidermodysplasia verruciformis.

**At a glance:** Pathogenic · review: Single submitter · rsID rs771079712 · 1 submitter · 1 linked condition · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the TMC8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to epidermodysplasia verruciformis.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TMC8 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Inherited epidermodysplasia verruciformis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seborrheic dermatitis — Very frequent (99-80%)
- Recurrent skin infections — Very frequent (99-80%)
- Abnormality of the immune system — Very frequent (99-80%)
- Papule — Very frequent (99-80%)
- Skin plaque — Very frequent (99-80%)
- Pustule — Very frequent (99-80%)
- Verrucae — Very frequent (99-80%)
- Hypopigmented skin patches — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006357/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMC8](https://sugi.bio/atlas/gene/TMC8/) |
| Protein change (HGVS p.) | p.Asp142fs |
| Coding change (HGVS c.) | c.423del |
| MANE Select transcript | [NM_152468](https://www.ncbi.nlm.nih.gov/nuccore/NM_152468) |
| dbSNP | [rs771079712](https://www.ncbi.nlm.nih.gov/snp/rs771079712/) |
| Variant type | Deletion |
| Location | chr17:78132483-78132483 (GRCh38) |
| ClinVar | [VCV1961021](https://www.ncbi.nlm.nih.gov/clinvar/variation/1961021/) |

**All HGVS expressions:** `LRG_118:g.4925del`, `LRG_119:g.6706del`, `LRG_119t1:c.423del`, `NC_000017.10:g.76128564del`, `NC_000017.11:g.78132483del`, `NG_007879.1:g.4925del`, `NG_007881.1:g.6706del`, `NM_152468.5:c.423del`

## 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 0.705, GERP -2.02 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.201, pLI 1.2654e-24. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 16**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 5.513**. 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 deletion 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 **0.00446%** (eas) · FAF95 0.00074% · FAF99 0.000277% · 2/44,824 in the highest group · 5/1,611,284 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,412 |
| Admixed American | 0.00167% | 59,812 |
| South Asian | 0.0011% | 90,732 |
| European (non-Finnish) | 8.48e-05% | 1,179,288 |

*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}

**TMC8** population constraint: LOEUF 1.201, pLI 1.2654e-24, missense-Z 0.019496; 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.77, 26% of residues very-high.

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

*Describes the biological roles of TMC8 (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:** TMC8's established molecular role includes tumor necrosis factor binding.


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

**Molecular function:** tumor necrosis factor binding, protein sequestering activity.

**Biological process:** intracellular zinc ion homeostasis, regulation of tumor necrosis factor-mediated signaling pathway, negative regulation of protein-containing complex assembly, negative regulation of protein binding, positive regulation of apoptotic process, negative regulation of canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-18.

**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 | 2025-03-18 |

## Associated conditions {#conditions}

[epidermodysplasia verruciformis](https://sugi.bio/atlas/disease/epidermodysplasia-verruciformis/).

**Reported phenotype names (ClinVar):** Epidermodysplasia verruciformis.

## Similar variants {#similar}

Related TMC8 variant pages (same residue, condition, or type): [TMC8 p.Arg295fs](/variant/tmc8-p-arg295fs), [TMC8 p.Ala188fs](/variant/tmc8-p-ala188fs), [TMC8 p.Asp251fs](/variant/tmc8-p-asp251fs), [TMC8 p.Gln236fs](/variant/tmc8-p-gln236fs), [TMC8 p.Gln291fs](/variant/tmc8-p-gln291fs), [TMC8 p.Glu425fs](/variant/tmc8-p-glu425fs), [TMC8 p.Leu300fs](/variant/tmc8-p-leu300fs), [TMC8 p.Leu583fs](/variant/tmc8-p-leu583fs).

### 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 1961021). 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.*