GeneBe

ZMIZ1

protein-coding

zinc finger MIZ-type containing 1, the group of Zinc fingers MIZ-type

Gene summary

This gene encodes a member of the PIAS (protein inhibitor of activated STAT) family of proteins. The encoded protein regulates the activity of various transcription factors, including the androgen receptor, Smad3/4, and p53. The encoded protein may also play a role in sumoylation. A translocation between this locus on chromosome 10 and the protein tyrosine kinase ABL1 locus on chromosome 9 has been associated with acute lymphoblastic leukemia. [provided by RefSeq, Mar 2010]

Previous symbols:
  • RAI17

MANE transcript

NM_020338.4

Inheritance

AD

ClinVar variants

P:58U:355B:274

Top phenotype

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr10:79,068,966-79,316,519

External References & Databases

Ensembl (ENSG00000108175)NCBI Gene (57178)OMIM (607159)HGNC:16493GenCCUniProt (Q9ULJ6)AlphaFoldClinVar (ZMIZ1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~247.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032855

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032855

Submitter: G2P

neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032855

Submitter: PanelApp Australia

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032855

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

ZMIZ1 (HGNC: 16493) located on 10q22, encodes a member of the PIAS (protein inhibitor of activated STAT) family of proteins. The protein acts as transcriptional coactivator in the TGF-beta signaling pathway by increasing the activity of the SMAD3/SMAD4 transcriptional complex (PMID:16777850). It is also involved in the transcriptional activation of a subset of NOTCH1 target genes including MYC, thymocyte and T cell development and in the regulation of postmitotic positioning of pyramidal neurons in the developing cerebral cortex (PMID:30639322). ZMIZ1 variants have been detected in a dozen of unrelated patients from different groups and in both sexes with common clinical features of neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (OMIM #607159). Associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, various other congenital malformations (PMID: 30639322; 31833199, 34680978). ZMIZ1 variants carriers show diverse phenotypes and being affected in multiple organs, thus ZMIZ1 is lumped to Complex neurodevelopmental disorder (MONDO:0100038). Identified ZMIZ1 variants show mostly de novo (PMID: 30639322; 35432459). In some cases, however, ZMIZ1 are found to be inherited from the parents (PMID: 34680978; 31833199). ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning (PMID: 30639322). Based on the consistent phenotypes; sufficient genetic and experimental evidence, ZMIZ1 is curated as “Definitive” for Complex neurodevelopmental disorder.

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 30639322Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZMIZ1 variants in ClinVar

13 Conditions Cataloged
not providedTotal: 645
Inborn genetic diseasesTotal: 155
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomaliesTotal: 79
ZMIZ1-related disorderTotal: 17
not specifiedTotal: 16
Syndromic neurodevelopmental disorderTotal: 13
See casesTotal: 3
Neurodevelopmental abnormalityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020338.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
8
clinvar
175
clinvar
17
clinvar
 201
missense
3
clinvar
5
clinvar
336
clinvar
63
clinvar
19
clinvar
 426
nonsense
6
clinvar
5
clinvar
 11
start loss
0
frameshift
10
clinvar
19
clinvar
4
clinvar
 33
splice donor/acceptor (+/-2bp)
9
clinvar
7
clinvar
 16
Total193935523836687

Highest pathogenic variant AF is 0.000004125634

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_020338.4RefSeqNP_065071.121MANE Select
ENST00000334512.10EnsemblENSP00000334474.521MANE Select
ENST00000880200.1EnsemblENSP00000550259.120Standard
ENST00000880200.2EnsemblENSP00000550259.120Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Androgen receptor signaling pathway
  • AndrogenReceptor
  • Coregulation of Androgen receptor activity

Biological Process

  • vasculogenesis
  • in utero embryonic development
  • heart morphogenesis
  • vitellogenesis
  • cell aging

Molecular Function

  • zinc ion binding

Cellular Component

  • nucleoplasm
  • cytoplasm
  • nuclear speck
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000334512
Coding exons
21
Length
247485
Individuals with no LoFs
125733
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125746
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.394476990.6390.00004447017
Missense (PolyPhen)129265.380.48612544
Synonymous-0.6843183031.050.00002242138
Loss of Function5.79752.10.1340.00000265521

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as transcriptional coactivator. Increases ligand- dependent transcriptional activity of AR and promotes AR sumoylation. The stimulation of AR activity is dependent upon sumoylation (PubMed:14609956, PubMed:26522984). Involved in transcriptional activation of a subset of NOTCH1 target genes including MYC. Involved in thymocyte and T cell development (By similarity). {ECO:0000250|UniProtKB:Q6P1E1, ECO:0000269|PubMed:14609956, ECO:0000269|PubMed:26522984}.;

Recessive Scores

pRec
0.123

Intolerance Scores

LoFtool
0.154
RVIS EVS
-2.04
RVIS percentile EVS
1.66

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.956

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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