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c.316-14T>C

SpliceS3Likely benignCytoplasmic · predicted
Splice variant · splice site near at position 106 · 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 106 (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 acceptor (3') 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, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1; Cataract 41; Wolfram-like syndrome; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
Population frequency (gnomAD v4)Ultra-rare · AF 0.0010%
cDNA changec.316-14T>C
ClinVar variantNM_006005.3(WFS1):c.316-14T>C
ClinVar accessionVCV000385813
Last evaluated2025/07/23 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

ClinVar classifies this variant as Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

  • Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
  • Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
  • Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
  • 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
  • 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 0.0010% · 15 / 1,453,900 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.0013%

Highest in European (non-Finnish): AF 0.0013% (14 of 1,108,910 alleles), in line with the global figure.

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.
Admixed American · under-sampled0.0023%1 / 43,7980—
European (non-Finnish)0.0013%14 / 1,108,9100~1 in 39600

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.316-14T>C 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.316-14T>C PDF card ↓or markdown ↓

Full Variant Card

c.316-14T_C — WFS1 Molecular Atlas Card

Variant type: Splice site Boundary: acceptor (3' splice site) · intronic offset -14 Nearest protein position: ~106 (N-terminal cytoplasmic (intrinsically disordered))

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

SpliceAI predicts little splicing disruption at this acceptor (3') 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: acceptor (3' splice site), extended splice region
  • SpliceAI delta scores (GRCh38 chr4:6288973 T>C):
    • 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 — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant)

ClinVar classifies this variant as Likely benign for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

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, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1; Cataract 41; Wolfram-like syndrome; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
  • cDNA change: c.316-14T>C
  • ClinVar accession: VCV000385813
  • Last evaluated: 2025/07/23 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (splice pipeline) on 2026-06-08T07:50:09.966343Z. Schema: reference/card_schema_extension.md (S1–S3). WFS1: UniProt O76024, AlphaFold v6.