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c.460+1G>A

SpliceS2PathogenicCytoplasmic · predicted
Splice variant · splice site near at position 154 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

S2 — Predicted frameshift skip of exon 4 (145 nt)

Interactive 3D Structure

Interactive structure
rotate · zoom · variant + 5 Å neighbors
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AlphaFold wild-type wolframin · the variant site near residue 154 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted.

Variant Assessment

Variant type
Splice
Schema
S2
Predicted frameshift skip of exon 4 (145 nt)
Domain
N-terminal cytoplasmic (intrinsically disordered)
Status
—

Therapeutic Implication · S2

SpliceAI predicts strong donor (5') loss (ΔS 1.00) -> skipping of exon 4 (145 nt, NOT divisible by 3), which shifts the reading frame downstream. A premature stop is predicted at ~aa 115. The frameshifted/truncated product follows the frameshift schema (F1/F2 by NMD); typically too compromised for chaperone rescue — gene-therapy track. (acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.96, donor-loss 1.00.)

Clinical Evidence

ClinVar classificationPathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditions—
Population frequency (gnomAD v4)Ultra-rare · AF 0.00021%
cDNA changec.460+1G>A
ClinVar variantNM_006005.3(WFS1):c.460+1G>A
ClinVar accessionVCV000004515
Last evaluated2024/10/23 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.

  • 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.

Population frequency
Global (all ancestries)
AF 0.00021% · 3 / 1,421,628 alleles
Homozygotes
0

Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.

No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.

Ancestry groupAllele freq.AC / ANHom.Carrier est.
Middle Eastern · under-sampled0.018%1 / 5,4840—
Remaining individuals · under-sampled0.0017%1 / 58,9320—
European (non-Finnish) · under-sampled0.000092%1 / 1,092,0420—

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.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.460+1G>A card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this S2 splice variant and its domain context.

Download c.460+1G>A PDF card ↓or markdown ↓

Full Variant Card

c.460+1G_A — WFS1 Molecular Atlas Card

Variant type: Splice site Boundary: donor (5' splice site) · intronic offset +1 Nearest protein position: ~154 (N-terminal cytoplasmic (intrinsically disordered))

Schema category: S2 — Predicted frameshift skip of exon 4 (145 nt)

SpliceAI predicts strong donor (5') loss (ΔS 1.00) -> skipping of exon 4 (145 nt, NOT divisible by 3), which shifts the reading frame downstream. A premature stop is predicted at ~aa 115. The frameshifted/truncated product follows the frameshift schema (F1/F2 by NMD); typically too compromised for chaperone rescue — gene-therapy track. (acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.96, donor-loss 1.00.)

Splice prediction

  • Affected site: donor (5' splice site), canonical (±1/±2 core)
  • SpliceAI delta scores (GRCh38 chr4:6289132 G>A):
    • acceptor gain 0.00 · acceptor loss 0.00
    • donor gain 0.96 · donor loss 1.00
  • Predicted outcome: Predicted frameshift skip of exon 4 (145 nt)

Clinical evidence

Inheritance and scope

Pathogenic — phenotype scope not stated in ClinVar

ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.

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
  • Review status: criteria provided, multiple submitters, no conflicts
  • cDNA change: c.460+1G>A
  • ClinVar accession: VCV000004515
  • Last evaluated: 2024/10/23 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (splice pipeline) on 2026-06-08T07:50:33.326616Z. Schema: reference/card_schema_extension.md (S1–S3). WFS1: UniProt O76024, AlphaFold v6.