ZSWIM6

protein-coding

zinc finger SWIM-type containing 6, the group of Zinc fingers SWIM-type

Gene summary

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]

MANE transcript

NM_020928.2

Inheritance

ClinVar variants

P:6U:469B:410

Top phenotype

Acromelic frontonasal dysostosis; Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:61,332,258-61,546,172

External References & Databases

Ensembl (ENSG00000130449)

Transcript & Mutation Effects

hg38 • Region Span ~213.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic featuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060642

Submitter: Labcorp Genetics (formerly Invitae)

acromelic frontonasal dysostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011359

Submitter: G2P

acromelic frontonasal dysostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011359

Submitter: PanelApp Australia

acromelic frontonasal dysostosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011359

Submitter: Labcorp Genetics (formerly Invitae)

acromelic frontonasal dysostosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011359

Submitter: Orphanet

neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic featuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060642

Submitter: PanelApp Australia

acromelic frontonasal dysostosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011359

Submitter: ClinGen

The *ZSWIM6* gene is located at chromosome 5q12.1, has 14 exons, and encodes a 133.kDa protein that belongs to a group of proteins described by the SWIM-type zinc finger domain. Multiple disease entities have been reported in association with this gene. According to criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism and phenotypic spectrum. Therefore, the following disease entities have been split into multiple disease entities: acromelic frontonasal dysostosis (OMIM:603671) and neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (OMIM:617865). Here, we curate autosomal dominant acromelic frontonasal dysostosis (MONDO:0011359). *ZSWIM6* was first reported in relation to autosomal dominant acromelic frontonasal dysostosis in 2014 (Smith et al., 2014, PMID: 25105228). Patients with this disease have been identified as heterozygous for a de novo missense mutation (c.3487C>T, p.Arg1163Trp) in the *ZSWIM6* gene. Smith et al 2014 postulate a gain-of-function effect of the mutation because of the differing phenotype in individuals with heterozygous deletions of the gene versus those diagnosed with acromelic frontonasal dysostosis. Common phenotypes for individuals with this variant include large fontanelle, hypertelorism, bifid nasal tip, nasal clefting, brachycephaly, median cleft face, carp-shaped mouth, interhemispheric lipoma, tibial hypoplasia/aplasia, symmetric preaxial polydactyly of the feet, bilateral clubbed foot, thickened nails of halluces, and intellectual disability. Due to the multitude of cases with this rare and distinct phenotype and the de novo occurrence in a highly constrained gene, the expert panel decided to award an additional 0.4 points per proband who has radiographic imaging and/or publicly available images. One missense variant in three publications (PMID: 25105228, 26706854, 33776626) and four clinical testing laboratories (SCV000568856.6, SCV004011595.1, SCV000742103.4, SCV000986913.2) have been included in this curation. De novo status has been confirmed for 12 out of the 14 probands reported here. This gene disease relationship is also supported by expression studies and a knockout mouse model (PMIDs: 25105228, 28433741). In summary, there is definitive evidence supporting the relationship between *ZSWIM6* and autosomal dominant acromelic frontonasal dysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 08/24/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Acromelic frontonasal dysostosis; Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic featuresAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25105228; 29198722

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZSWIM6 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 908

Inborn genetic diseasesTotal: 179

not specifiedTotal: 120

ZSWIM6-related disorderTotal: 47

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic featuresTotal: 45

Acromelic frontonasal dysostosisTotal: 30

See casesTotal: 3

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020928.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	283 clinvar	4 clinvar	295
missense		3 clinvar	440 clinvar	89 clinvar	32 clinvar	564
nonsense		2 clinvar	5 clinvar			7
start loss			1 clinvar			1
frameshift	1 clinvar		13 clinvar	2 clinvar		16
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	5	469	374	36	885

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020928.2	RefSeq	NP_065979.1	14	MANE Select
ENST00000252744.6	Ensembl	ENSP00000252744.5	14	MANE Select
ENST00001132195.1	Ensembl	ENSP00000802631.1	14	Standard
XM_017009677.2	RefSeq	XP_016865166.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of axon guidance

Molecular Function

zinc ion binding

Cellular Component

Cul2-RING ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252744
Coding exons: 14
Length: 213898
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.18	291	572	0.509	0.0000329	7868
Missense (PolyPhen)		80	229.16	0.34911		2716
Synonymous	1.28	190	214	0.889	0.0000120	2472
Loss of Function	6.17	0	44.3	0.00	0.00000238	570

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Acromelic frontonasal dysostosis (AFND) [MIM:603671]: A rare variant form of frontonasal dysplasia, an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism, broadening of the nasal root, median facial cleft affecting the nose and/or upper lip and palate, unilateral or bilateral clefting of the alae nasi, lack of formation of the nasal tip, anterior cranium bifidum occultum, a V-shaped or widow's peak frontal hairline. AFND is characterized by the association of frontonasal malformations with various combinations of polydactyly, tibial hypoplasia, epibulbar dermoid, encephalocoele, corpus callosum agenesis and Dandy-Walker malformation. {ECO:0000269|PubMed:25105228}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA) [MIM:617865]: An autosomal dominant neurodevelopmental disorder characterized by infantile-onset global developmental delay, severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy. {ECO:0000269|PubMed:29198722}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: 0.19
RVIS percentile EVS: 67.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.561

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High