# NM_001353214.3(DYM):c.99G>A (p.Trp33Ter)

https://sugi.bio/variant/dym-p-trp33ter

## Summary

**DYM p.Trp33Ter (c.99G>A)** is classified **Likely pathogenic** in DYM (ClinVar, Single submitter, 1 submitter). Absent from gnomAD v4.1; Associated with Dyggve-Melchior-Clausen disease.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2524201617 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DYM gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Dyggve-Melchior-Clausen disease.

*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) | Infancy |
| Diagnostic panels | DYM is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Dyggve-Melchior-Clausen disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Spondyloepimetaphyseal dysplasia — Very frequent (99-80%)
- Disproportionate short-trunk short stature — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Coarse facial features — Frequent (79-30%)
- Short neck — Frequent (79-30%)
- Pectus carinatum — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006295/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYM](https://sugi.bio/atlas/gene/DYM/) |
| Protein change (HGVS p.) | p.Trp33Ter |
| Coding change (HGVS c.) | c.99G>A |
| MANE Select transcript | [NM_001353214](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353214) |
| dbSNP | [rs2524201617](https://www.ncbi.nlm.nih.gov/snp/rs2524201617/) |
| Variant type | single nucleotide variant |
| Location | chr18:49430296-49430296 (GRCh38) |
| ClinVar | [VCV2584904](https://www.ncbi.nlm.nih.gov/clinvar/variation/2584904/) |

**All HGVS expressions:** `NC_000018.10:g.49430296C>T`, `NC_000018.9:g.46956666C>T`, `NG_009239.2:g.35438G>A`, `NG_009239.3:g.35349G>A`, `NM_001353210.3:c.99G>A`, `NM_001353211.3:c.99G>A`, `NM_001353212.3:c.99G>A`, `NM_001353213.3:c.99G>A`, `NM_001353214.3:c.99G>A`, `NM_001353215.3:c.99G>A`, `NM_001353216.3:c.99G>A`, `NM_001374428.1:c.99G>A`, `NM_001374429.1:c.99G>A`, `NM_001374430.1:c.99G>A`, `NM_001374431.1:c.99G>A`, `NM_001374432.1:c.99G>A`, `NM_001374433.1:c.99G>A`, `NM_001374434.1:c.99G>A`, `NM_001374435.1:c.99G>A`, `NM_001374436.1:c.99G>A`, `NM_001374437.1:c.99G>A`, `NM_001374438.1:c.99G>A`, `NM_001374439.1:c.99G>A`, `NM_001374440.1:c.99G>A`, `NM_001374441.1:c.99G>A`, `NM_001374442.1:c.99G>A`, `NM_001374443.1:c.99G>A`, `NM_001374444.1:c.99G>A`, `NM_017653.6:c.99G>A`

## 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 7.504, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.081, pLI 7.9636e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**DYM** population constraint: LOEUF 1.081, pLI 7.9636e-21, missense-Z 0.92126; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 87.91, 72% of residues very-high.

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

*Describes the biological roles of DYM (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:** DYM's established molecular role includes enzyme binding.


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

**Molecular function:** enzyme binding.

**Biological process:** Golgi organization, bone development.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[Dyggve-Melchior-Clausen disease](https://sugi.bio/atlas/disease/dyggve-melchior-clausen-disease/).

**Reported phenotype names (ClinVar):** Dyggve-Melchior-Clausen syndrome, Dyggve-Melchior-Clausen disease, DMC syndrome.

## Same-residue context {#hotspot}

Residue **33** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DYM p.Trp33fs](/variant/dym-p-trp33fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DYM variant pages (same residue, condition, or type): [DYM p.Trp33fs](/variant/dym-p-trp33fs), [DYM c.1728+2T>C](/variant/dym-c-1728-plus-2t-c), [DYM c.947-2A>G](/variant/dym-c-947-minus-2a-g), [DYM p.Arg204Ter](/variant/dym-p-arg204ter), [DYM p.Arg428Ter](/variant/dym-p-arg428ter), [DYM p.Arg588Ter](/variant/dym-p-arg588ter), [DYM p.Arg70Ter](/variant/dym-p-arg70ter), [DYM p.Gln306Ter](/variant/dym-p-gln306ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2584904). 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.*