GLIS3

protein-coding

GLIS family zinc finger 3, the group of Zinc fingers C2H2-type

Gene summary

This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear protein with five C2H2-type zinc finger domains. This protein functions as both a repressor and activator of transcription and is specifically involved in the development of pancreatic beta cells, the thyroid, eye, liver and kidney. Mutations in this gene have been associated with neonatal diabetes and congenital hypothyroidism (NDH). Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only two have been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

ZNF515

MANE transcript

NM_001042413.2

Inheritance

ClinVar variants

P:20U:369B:178

Top phenotype

Diabetes mellitus, neonatal, with congenital hypothyroidism

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr9:3,824,127-4,348,392

External References & Databases

Ensembl (ENSG00000107249)

Transcript & Mutation Effects

hg38 • Region Span ~524.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neonatal diabetes mellitus with congenital hypothyroidismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: Ambry Genetics

neonatal diabetes mellitus with congenital hypothyroidismSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: Orphanet

neonatal diabetes mellitus with congenital hypothyroidismDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: G2P

Tourette syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

neonatal diabetes mellitus with congenital hypothyroidismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: Genomics England PanelApp

neonatal diabetes mellitus with congenital hypothyroidismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: PanelApp Australia

neonatal diabetes mellitus with congenital hypothyroidismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Diabetes mellitus, neonatal, with congenital hypothyroidismAR

Manifestation: Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Endocrine

Rationale: Prompt treatment (eg, of ketoacidosis and dehydration) can avoid morbidity; Treatment of congenital hypothyroidism can improve outcome

Refs: 12966531; 16715098

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLIS3 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 297

Neonatal diabetes mellitus with congenital hypothyroidismTotal: 285

Inborn genetic diseasesTotal: 159

GLIS3-related disorderTotal: 83

not specifiedTotal: 30

Monogenic diabetesTotal: 29

Transitory neonatal diabetes mellitusTotal: 11

Diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042413.2. 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			12 clinvar	130 clinvar	2 clinvar	144
missense	2 clinvar		349 clinvar	41 clinvar	5 clinvar	397
nonsense	3 clinvar	6 clinvar	3 clinvar			12
start loss		1 clinvar	1 clinvar			2
frameshift	2 clinvar	5 clinvar				7
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	7	13	369	171	7	567

Highest pathogenic variant AF is 0.000027262307

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001042413.2	RefSeq	NP_001035878.1	10	MANE Select
ENST00000381971.8	Ensembl	ENSP00000371398.3	10	MANE Select
NM_001438906.1	RefSeq	NP_001425835.1	10	Standard
NM_001438907.1	RefSeq	NP_001425836.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
glis3	Danio rerio	Structure: pancreatic B cell Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

glis3

Danio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381971
Coding exons: 10
Length: 524266
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-3.14	772	563	1.37	0.0000361	5976
Missense (PolyPhen)		323	254.47	1.2693		2904
Synonymous	-4.73	343	248	1.38	0.0000185	1951
Loss of Function	2.81	18	36.3	0.496	0.00000207	391

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00065	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as both a repressor and activator of transcription. Binds to the consensus sequence 5'-GACCACCCAC-3' (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.531
RVIS EVS: -0.01
RVIS percentile EVS: 52.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.744

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium