MAFA

protein-coding

MAF bZIP transcription factor A, the group of Basic leucine zipper proteins

Gene summary

MAFA is a transcription factor that binds RIPE3b, a conserved enhancer element that regulates pancreatic beta cell-specific expression of the insulin gene (INS; MIM 176730) (Olbrot et al., 2002 [PubMed 12011435]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_201589.4

Inheritance

ClinVar variants

P:2U:69B:17

Top phenotype

Insulinomatosis and diabetes mellitus syndrome

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr8:143,419,182-143,430,732

External References & Databases

Ensembl (ENSG00000182759)

Transcript & Mutation Effects

hg38 • Region Span ~11.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Insulinomatosis and diabetes mellitus syndromeAD

Manifestation: Endocrine; Oncologic; Ophthalmologic

Intervention: Endocrine; Oncologic; Ophthalmologic

Rationale: The condition can include hypoglycemia due to insulomas, and management (with diazoxide and diet, though surgery has also been described) has been described as beneficial; Individuals have been described with glaucoma, and awareness may allow early diagnosis and management

Refs: 19011561; 29339498

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAFA variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 74

MAFA-related disorderTotal: 13

Islet cell adenomatosisTotal: 9

not providedTotal: 3

Osteopetrosis, autosomal dominant 3Total: 1

Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_201589.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				6 clinvar	3 clinvar	9
missense	1 clinvar	1 clinvar	69 clinvar	6 clinvar	2 clinvar	79
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	1	69	12	5	88

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_201589.4	RefSeq	NP_963883.2	1	MANE Select
ENST00000333480.3	Ensembl	ENSP00000328364.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Type II diabetes mellitus - Homo sapiens (human)
Maturity onset diabetes of the young - Homo sapiens (human)
Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
Tacrolimus/Cyclosporine Pathway, Pharmacodynamics
Type II diabetes mellitus

Biological Process

regulation of transcription, DNA-templated
nitric oxide mediated signal transduction
response to glucose
insulin secretion
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein homodimerization activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000333480
Coding exons: 1
Length: 11225
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	0.610	109	128	0.849	0.00000604	2225
Missense (PolyPhen)		34	38.899	0.87406		530
Synonymous	1.39	45	58.5	0.770	0.00000295	733
Loss of Function	0.490	4	5.21	0.768	2.23e-7	77

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

Function: FUNCTION: Transcription factor that activates insulin gene expression (PubMed:15993959, PubMed:12011435). Acts synergistically with NEUROD1/BETA2 and PDX1 (PubMed:15993959). Binds the insulin enhancer C1/RIPE3b element (PubMed:12011435). Binds to consensus TRE-type MARE 5'-TGCTGACTCAGCA-3' DNA sequence (PubMed:23148532, PubMed:29339498). {ECO:0000269|PubMed:12011435, ECO:0000269|PubMed:15993959, ECO:0000269|PubMed:23148532, ECO:0000269|PubMed:29339498}.;
Disease: DISEASE: Insulinomatosis and diabetes mellitus (INSDM) [MIM:147630]: An autosomal dominant disorder characterized by the occurrence of multicentric insulinomas, hyperinsulinemic hypoglycemia, non insulin-dependent diabetes mellitus, and impaired glucose tolerance. Some patients also exhibit congenital cataract and/or congenital glaucoma. {ECO:0000269|PubMed:29339498}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.834

Gene Damage Prediction

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