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c.316-164A>G

SpliceS3Likely benignCytoplasmic · predicted
Splice variant · splice site near at position 106 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

S3 — Cryptic donor activation predicted (SpliceAI ΔS 0.53)

Interactive 3D Structure

Interactive structure
rotate · zoom · variant + 5 Å neighbors
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AlphaFold wild-type wolframin · the variant site near residue 106 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted.

Variant Assessment

Variant type
Splice
Schema
S3
Cryptic donor activation predicted (SpliceAI ΔS 0.53)
Domain
N-terminal cytoplasmic (intrinsically disordered)
Status
—

Therapeutic Implication · S3

SpliceAI's strongest signal is a NEW cryptic donor site (ΔS 0.53, ~+0 nt from the variant; acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.53, donor-loss 0.06). Cryptic activation produces a non-canonical junction whose reading-frame impact depends on the exact cryptic position — typically a partial exon gain/loss. Outcome is context-dependent; wet-lab RNA validation required. Flagged S3.

Clinical Evidence

ClinVar classificationBenign/Likely benign
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.316-164A>G
ClinVar variantNM_006005.3(WFS1):c.316-164A>G
ClinVar accessionVCV000672589
Last evaluated2018/06/14 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Classified for2★ documented assertion

ClinVar classifies this variant as Benign/Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.

  • Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
  • 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)
Absent from gnomAD v4
Homozygotes
Not available

No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.

No homozygotes — the variant is absent from gnomAD v4 altogether.

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.316-164A>G card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this S3 splice variant and its domain context.

Download c.316-164A>G PDF card ↓or markdown ↓

Full Variant Card

c.316-164A_G — WFS1 Molecular Atlas Card

Variant type: Splice site Boundary: acceptor (3' splice site) · intronic offset -164 Nearest protein position: ~106 (N-terminal cytoplasmic (intrinsically disordered))

Schema category: S3 — Cryptic donor activation predicted (SpliceAI ΔS 0.53)

SpliceAI's strongest signal is a NEW cryptic donor site (ΔS 0.53, ~+0 nt from the variant; acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.53, donor-loss 0.06). Cryptic activation produces a non-canonical junction whose reading-frame impact depends on the exact cryptic position — typically a partial exon gain/loss. Outcome is context-dependent; wet-lab RNA validation required. Flagged S3.

Splice prediction

  • Affected site: acceptor (3' splice site), extended splice region
  • SpliceAI delta scores (GRCh38 chr4:6288823 A>G):
    • acceptor gain 0.00 · acceptor loss 0.00
    • donor gain 0.53 · donor loss 0.06
  • Predicted outcome: Cryptic donor activation predicted (SpliceAI ΔS 0.53)

Clinical evidence

Inheritance and scope

Benign/Likely benign — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)

ClinVar classifies this variant as Benign/Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.

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: Benign/Likely benign
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.316-164A>G
  • ClinVar accession: VCV000672589
  • Last evaluated: 2018/06/14 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (splice pipeline) on 2026-06-08T07:50:13.551018Z. Schema: reference/card_schema_extension.md (S1–S3). WFS1: UniProt O76024, AlphaFold v6.