c.712+16G>A
SpliceS3Likely benignCytoplasmic · predictedS3 — Minimal predicted splicing impact (SpliceAI ΔS 0.01)
Interactive 3D Structure
AlphaFold wild-type wolframin · the variant site near residue 238 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted.
Variant Assessment
Therapeutic Implication · S3
Clinical Evidence
Observed in the general population.
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.
Highest in Ashkenazi Jewish: AF 1.83% (535 of 29,194 alleles), 7.0x the global figure. The global AF describes the general population, not the at-risk group.
22 homozygotes reported in gnomAD v4 (8 Ashkenazi Jewish; 2 Middle Eastern; 9 South Asian; 3 European (non-Finnish)). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Ashkenazi Jewish | 1.83% | 535 / 29,194 | 8 | ~1 in 27 |
| Middle Eastern | 1.52% | 85 / 5,598 | 2 | ~1 in 33 |
| South Asian | 0.653% | 573 / 87,798 | 9 | ~1 in 77 |
| Remaining individuals | 0.387% | 239 / 61,792 | 0 | ~1 in 130 |
| Admixed American | 0.257% | 148 / 57,618 | 0 | ~1 in 190 |
| European (non-Finnish) | 0.221% | 2,594 / 1,172,432 | 3 | ~1 in 230 |
| African / African American | 0.039% | 29 / 74,726 | 0 | ~1 in 1290 |
| Finnish | 0.0032% | 2 / 61,564 | 0 | ~1 in 15390 |
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.
Feed this card to Wolfram Intelligence
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Full Variant Card
c.712+16G_A — WFS1 Molecular Atlas Card
Variant type: Splice site Boundary: donor (5' splice site) · intronic offset +16 Nearest protein position: ~238 (N-terminal cytoplasmic (intrinsically disordered))
Schema category: S3 — Minimal predicted splicing impact (SpliceAI ΔS 0.01)
SpliceAI predicts little splicing disruption at this donor (5') site (max ΔS 0.01 < 0.2; acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.01, donor-loss 0.00). The variant may be tolerated or act through a weak/again-tissue-specific mechanism; wet-lab RNA validation is the arbiter before any therapeutic call.
Splice prediction
- Affected site: donor (5' splice site), extended splice region
- SpliceAI delta scores (GRCh38 chr4:6292013 G>A):
- acceptor gain 0.00 · acceptor loss 0.00
- donor gain 0.01 · donor loss 0.00
- Predicted outcome: Minimal predicted splicing impact (SpliceAI ΔS 0.01)
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.712+16G>A
- ClinVar accession: VCV000215380
- Last evaluated: 2026/03/01 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (splice pipeline) on 2026-06-08T07:51:50.505307Z.
Schema: reference/card_schema_extension.md (S1–S3). WFS1: UniProt O76024, AlphaFold v6.