ZSWIM6

Chr 5AD

zinc finger SWIM-type containing 6

Also known as: AFND, NEDMAGA

NCBI Gene: 57688 ENSG00000130449 UniProt: Q9HCJ5 OMIM: 615951

The protein contains a zinc finger SWIM domain and is involved in nervous system development, particularly striatal morphology and motor regulation. Mutations cause acromelic frontonasal dysostosis and neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants, indicating critical importance for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.072 OMIM phenotypes

Clinical Summary— ZSWIM6

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Gene-Disease Validity (ClinGen)

acromelic frontonasal dysostosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 133 VUS of 200 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.07LOEUF

pLI 1.000

Z-score 6.17

OE 0.00 (0.00–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

4.18Z-score

OE missense 0.51 (0.46–0.56)

291 obs / 572.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.07)

0≤0.351.4

Missense OE0.51 (0.46–0.56)

0≤0.61.4

Synonymous OE0.89

0≤1.21.6

LoF obs/exp: 0 / 44.3Missense obs/exp: 291 / 572.0Syn Z: 1.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongZSWIM6-related acromelic frontonasal dysostosisGOFAD

0.2399th %ile

GOF

0.4382th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.07

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThis finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect.PMID:29198722

GOFA recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gainPMID:29198722

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.