ZSWIM6

Chr 5

zinc finger SWIM-type containing 6

Also known as: AFND, NEDMAGA

NCBI Gene: 57688 ENSG00000130449 UniProt: Q9HCJ5

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.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene contains a zinc finger SWI2/SNF2 and MuDR (SWIM) domain. Proteins with SWIM domains have been found in a diverse number of species and are predicted to interact with DNA or proteins. Mutations in this gene result in acromelic frontonasal dysostosis. [provided by RefSeq, Apr 2017]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.07

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

5 unique Pathogenic / Likely Pathogenic· 487 VUS of 1053 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.00 (0.00–0.07)

0≤0.351.4

Missense OE?0.51 (0.46–0.56)

0≤0.61.4

Synonymous OE?0.89

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

This gene — mechanism propensity

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 · 40% of P/LP variants are LoF · 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.1

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 gain1

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

References

1.PMID 29198722 ↗

ClinVar Variant Classifications

1053 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS487

Likely Benign429

Benign73

Conflicting54

Pathogenic

Likely Pathogenic

487

VUS

429

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	3	0	0	4
VUS	17	437	26	7	487
Likely Benign	2	63	104	260	429
Benign	0	37	24	12	73
Conflicting	—				54
Total	21	540	154	279	1,048

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ZSWIM6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →