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W540*

NonsenseN3PathogenicTransmembrane · predicted
Nonsense variant · truncation point at position 540 · Transmembrane helix 8 · WFS1 (Wolframin)

N3 — NMD-escape, moderate truncation — chaperone exploration

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — truncation point at residue 540
Fullscreen ↗
Translated product
Native sequence to residue 539; everything highlighted (residues 540–890) is lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 540 marked. Right: the same model with the lost region (residues 540–890) marked — what the nonsense transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Nonsense
NMD status
NMD-escape
high confidence
Schema
N3
NMD-escape, moderate truncation — chaperone exploration
Native protein retained
60.6%

Stop codon at position 540 is in the last exon (exon 8, starts ~aa 413). NMD does not target stop codons in the last exon — a truncated protein is produced.

Therapeutic Implication · N3

Truncated protein retains substantial structure but loses C-terminal domains. Worth screening generic ER chaperones (4-PBA, TUDCA) and sigma-1 receptor agonists. Lower confidence than for missense variants, but a candidate for the high-content drug screen (Initiative 8).

Protein Domains

Retained (aa 1–539)
  • N-terminal cytoplasmic (intrinsically disordered)1–310
  • Transmembrane helix 1311–331
  • Cytoplasmic loop 1332–340
  • Transmembrane helix 2341–361
  • Lumenal loop 1362–370
  • Transmembrane helix 3371–391
  • Cytoplasmic loop 2392–400
  • Transmembrane helix 4401–421
  • Lumenal loop 2422–431
  • Transmembrane helix 5432–452
  • Cytoplasmic loop 3453–461
  • Transmembrane helix 6462–482
  • Lumenal loop 3483–496
  • Transmembrane helix 7497–517
  • Cytoplasmic loop 4518–532
Lost / non-native (downstream)
  • Lumenal loop 4554–573
  • Transmembrane helix 9574–594
  • Cytoplasmic loop 5 / pre-lumenal595–599
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)600–890

Clinical Evidence

ClinVar classificationPathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.00020%
cDNA changec.1620G>A
ClinVar variantNM_006005.3(WFS1):c.1620G>A (p.Trp540Ter)
ClinVar accessionVCV000929945
Last evaluated2024/04/16 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

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Full Variant Card

W540* — WFS1 Molecular Atlas Card

Variant type: Nonsense (premature stop codon) Position: 540 Wild-type residue: Tryptophan (W) Domain context (where the stop falls): Transmembrane helix 8

Schema category: N3 — NMD-escape, moderate truncation — chaperone exploration

Truncated protein retains substantial structure but loses C-terminal domains. Worth screening generic ER chaperones (4-PBA, TUDCA) and sigma-1 receptor agonists. Lower confidence than for missense variants, but a candidate for the high-content drug screen (Initiative 8).

NMD prediction

  • Status: NMD-escape
  • Confidence: high
  • Reasoning: Stop codon at position 540 is in the last exon (exon 8, starts ~aa 413). NMD does not target stop codons in the last exon — a truncated protein is produced.

Truncation analysis

  • Residues retained: 1 – 539 (60.6% of full-length protein)
  • Residues lost: 540 – 890 (39.4% of full-length protein)

Retained domains

  • N-terminal cytoplasmic (intrinsically disordered) (aa 1–310)
  • Transmembrane helix 1 (aa 311–331)
  • Cytoplasmic loop 1 (aa 332–340)
  • Transmembrane helix 2 (aa 341–361)
  • Lumenal loop 1 (aa 362–370)
  • Transmembrane helix 3 (aa 371–391)
  • Cytoplasmic loop 2 (aa 392–400)
  • Transmembrane helix 4 (aa 401–421)
  • Lumenal loop 2 (aa 422–431)
  • Transmembrane helix 5 (aa 432–452)
  • Cytoplasmic loop 3 (aa 453–461)
  • Transmembrane helix 6 (aa 462–482)
  • Lumenal loop 3 (aa 483–496)
  • Transmembrane helix 7 (aa 497–517)
  • Cytoplasmic loop 4 (aa 518–532)

Partially retained at truncation point

  • Transmembrane helix 8 — partial: aa 533–539 retained, aa 540–553 lost

Lost domains

  • Lumenal loop 4 (aa 554–573)
  • Transmembrane helix 9 (aa 574–594)
  • Cytoplasmic loop 5 / pre-lumenal (aa 595–599)
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (aa 600–890)

Clinical evidence

  • Classification: Pathogenic
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1
  • cDNA change: c.1620G>A
  • ClinVar accession: VCV000929945
  • Last evaluated: 2024/04/16 00:00
  • Submissions: 2

Why this variant matters

Moderate truncation leaves some of the protein intact, including portions of the transmembrane bundle. Whether the partial protein can be coaxed into function with chaperones is an open question — the atlas surfaces it as a candidate for the Initiative 8 drug screen, with the explicit structural data needed to design that screen.

Card generated by wolfram-atlas-batch skill (v1) on 2026-06-08T02:18:18.198989Z. NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md. WFS1 reference: UniProt O76024, AlphaFold model v6.