c.911_914dup
FrameshiftF1Pathogenic/Likely pathogenicCytoplasmic · predictedF1 — Frameshift, NMD-targeted — null allele
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 306 marked. Right: the same model with the non-native (scrambled) and lost region (residues 306–890) marked — what the frameshift transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 306 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.
Therapeutic Implication · F1
Protein Domains
- 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
- Transmembrane helix 8533–553
- 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Remaining individuals: AF 0.0032% (2 of 62,484 alleles), 5.7x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Remaining individuals | 0.0032% | 2 / 62,484 | 0 | ~1 in 15620 |
| European (non-Finnish) | 0.00059% | 7 / 1,179,998 | 0 | ~1 in 84290 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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Full Variant Card
c.911_914dup — WFS1 Molecular Atlas Card
Variant type: Frameshift Frameshift point: residue 306 Predicted premature stop (PTC): residue 306 Domain context (where the frame breaks): N-terminal cytoplasmic (intrinsically disordered)
Schema category: F1 — Frameshift, NMD-targeted — null allele
The frameshift creates a premature termination codon well upstream of the last exon-exon junction; the 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No frameshifted protein is produced — functionally a null allele. Therapeutic options: (a) translational readthrough drugs (Ataluren/PTC124, aminoglycosides) — notably LESS effective for frameshifts than for nonsense variants, because reading through the PTC still yields out-of-frame protein; (b) gene therapy via allele replacement is the higher-yield path.
Premature-stop prediction
- Frameshift point: aa 306
- Predicted PTC: aa 306 (0 codons downstream of the frame break)
- Method: deterministic translation of edited NM_006005.3 CDS (frameshift position = first changed residue, HGVS convention)
- Confidence: high
NMD prediction
- Status: NMD-targeted
- Confidence: high
- Reasoning: Stop codon at position 306 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.
Protein consequence
- Native (wild-type) sequence retained: aa 1 – 305 (34.3% of full-length protein)
- Non-native scrambled stretch: aa 306 – 305 (0 residues of out-of-frame sequence)
- Lost beyond the PTC: aa 306 – 890 (585 residues)
Native domains retained (upstream of the frameshift)
(no domains fully retained)
Domain interrupted at the frameshift point
- N-terminal cytoplasmic (intrinsically disordered) — native aa 1–305 retained; aa 306–310 replaced by non-native sequence
Native domains downstream of the frameshift (lost or non-native)
- 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)
- Transmembrane helix 8 (aa 533–553)
- 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
Inheritance and scope
Pathogenic/Likely pathogenic — for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296)
ClinVar classifies this variant as Pathogenic/Likely pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
- Classification: Pathogenic/Likely pathogenic
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: WFS1-related disorder; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Wolfram-like syndrome
- cDNA change: c.911_914dup
- ClinVar accession: VCV000215405
- Last evaluated: 2024/05/01 00:00
- Submissions: 1
Why this variant matters
The frame breaks early enough that the premature stop is caught by nonsense-mediated decay — the transcript is degraded before any out-of-frame protein accumulates. That makes this, in effect, a clean null allele: the atlas points the therapeutic conversation at gene replacement, and notes that readthrough drugs are a weaker fit here than for true nonsense variants because reading through the stop still yields scrambled protein.
Card generated by wolfram-atlas-batch skill (v2 — frameshift pipeline) on 2026-06-08T02:17:13.827307Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
CDS reference: NM_006005.3 (171..2843). WFS1 reference: UniProt O76024, AlphaFold model v6.