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c.861+19G>A

SpliceS3Likely benignCytoplasmic · predicted
Splice variant · splice site near at position 287 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

S3 — Minimal predicted splicing impact (SpliceAI ΔS 0.00)

Interactive 3D Structure

Interactive structure
rotate · zoom · variant + 5 Å neighbors
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AlphaFold wild-type wolframin · the variant site near residue 287 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted.

Variant Assessment

Variant type
Splice
Schema
S3
Minimal predicted splicing impact (SpliceAI ΔS 0.00)
Domain
N-terminal cytoplasmic (intrinsically disordered)
Status
—

Therapeutic Implication · S3

SpliceAI predicts little splicing disruption at this donor (5') site (max ΔS 0.00 < 0.2; acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.00, 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.

Clinical Evidence

ClinVar classificationLikely benign
Review statuscriteria provided, single submitter
Associated conditions—
Population frequency (gnomAD v4)Ultra-rare · AF 0.0032%
cDNA changec.861+19G>A
ClinVar variantNM_006005.3(WFS1):c.861+19G>A
ClinVar accessionVCV001534015
Last evaluated2025/12/01 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

ClinVar classifies this variant as Likely benign, 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: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.

Population frequency
Global (all ancestries)
AF 0.0032% · 51 / 1,610,306 alleles
Homozygotes
0
Highest-frequency population
Middle Eastern · AF 0.043%

Highest in Middle Eastern: AF 0.043% (2 of 4,656 alleles), 13.6x 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 groupAllele freq.AC / ANHom.Carrier est.
Middle Eastern0.043%2 / 4,6560~1 in 1160
African / African American0.020%15 / 74,8300~1 in 2490
Admixed American0.0033%2 / 59,9980~1 in 15000
European (non-Finnish)0.0025%30 / 1,179,9960~1 in 19670
Remaining individuals · under-sampled0.0016%1 / 62,3000—
South Asian · under-sampled0.0011%1 / 90,9900—

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.861+19G>A card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this S3 splice variant and its domain context.

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Full Variant Card

c.861+19G_A — WFS1 Molecular Atlas Card

Variant type: Splice site Boundary: donor (5' splice site) · intronic offset +19 Nearest protein position: ~287 (N-terminal cytoplasmic (intrinsically disordered))

Schema category: S3 — Minimal predicted splicing impact (SpliceAI ΔS 0.00)

SpliceAI predicts little splicing disruption at this donor (5') site (max ΔS 0.00 < 0.2; acceptor-gain 0.00, acceptor-loss 0.00, donor-gain 0.00, 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 chr4:6295208 G>A):
    • acceptor gain 0.00 · acceptor loss 0.00
    • donor gain 0.00 · donor loss 0.00
  • Predicted outcome: Minimal predicted splicing impact (SpliceAI ΔS 0.00)

Clinical evidence

Inheritance and scope

Likely benign — phenotype scope not stated in ClinVar

ClinVar classifies this variant as Likely benign, 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: Likely benign
  • Review status: criteria provided, single submitter
  • cDNA change: c.861+19G>A
  • ClinVar accession: VCV001534015
  • Last evaluated: 2025/12/01 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (splice pipeline) on 2026-06-08T07:53:22.271487Z. Schema: reference/card_schema_extension.md (S1–S3). WFS1: UniProt O76024, AlphaFold v6.