c.1060_1062del

In-frame indelI1ConflictingTransmembrane · predicted

In-frame indel variant · indel site at position 354 · Transmembrane helix 2 · WFS1 (Wolframin)

I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

Wild-type vs Modified Structure

Wild-type · full length

Wild-type wolframin · 890 aa — AlphaFold reference

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Modified product

Modified product · c.1060_1062del — Cα-RMSD 3.68 Å vs WT (folded core)

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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 1-aa in-frame deletion product — the affected region near residue 354 (Transmembrane helix 2) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 3.68 Å.

Variant Assessment

Variant type

In-frame indel

Schema

Single-residue deletion in a transmembrane helix — likely catastrophic kink

Domain

Transmembrane helix 2

Backbone Cα-RMSD

3.68 Å

vs WT · folded core (n=178)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.3) and superposed on the wild-type AlphaFold model. Kabsch-superposed Cα-RMSD over high-confidence (WT pLDDT>70) residues N-terminal to the lesion; cross-pipeline, includes ~few-Å method baseline

Therapeutic Implication · I1

A single residue removed inside Transmembrane helix 2 shifts the helical register, which typically kinks or unwinds the helix and disrupts membrane insertion — structurally similar to a severe TM missense. Gene therapy track. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Cataract 41; Wolfram-like syndrome; Type 2 diabetes mellitus; Wolfram syndrome 1; Monogenic diabetes; Rare genetic deafness

Population frequency (gnomAD v4)Ultra-rare · AF 0.0019%

cDNA changec.1060_1062del

ClinVar variantNM_006005.3(WFS1):c.1060_1062del (p.Phe354del)

ClinVar accessionVCV000228420

Last evaluated2025/12/27 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Hearing loss, inheritance unstated (inheritance not specified). 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.

Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus; Monogenic diabetes
Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness

Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.

Population frequency

Global (all ancestries)

AF 0.0019% · 31 / 1,614,110 alleles

Homozygotes

Highest-frequency population

European (non-Finnish) · AF 0.0024%

Highest in European (non-Finnish): AF 0.0024% (28 of 1,180,020 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 group	Allele freq.	AC / AN	Carrier est.
European (non-Finnish)	0.0024%	28 / 1,180,020	~1 in 21070
South Asian	0.0022%	2 / 91,076	~1 in 22770
Remaining individuals · under-sampled	0.0016%	1 / 62,510	—

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.1060_1062del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I1 in-frame indel variant and its domain context.

Download c.1060_1062del PDF card ↓or markdown ↓

Full Variant Card

c.1060_1062del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 354 Domain context: Transmembrane helix 2

Schema category: I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

Structural prediction

Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
Affected domain: Transmembrane helix 2
Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

Inheritance and scope

Conflicting classifications of pathogenicity — for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Hearing loss, inheritance unstated (inheritance not specified)

Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes. 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: Conflicting classifications of pathogenicity
Review status: criteria provided, conflicting classifications
Associated conditions: Autosomal dominant nonsyndromic hearing loss 6; Cataract 41; Wolfram-like syndrome; Type 2 diabetes mellitus; Wolfram syndrome 1; Monogenic diabetes; Rare genetic deafness
cDNA change: c.1060_1062del
ClinVar accession: VCV000228420
Last evaluated: 2025/12/27 00:00
Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:00.221742Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.