MITF

melanocyte inducing transcription factor, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 3:69739456-69968336

Previous symbols: [ "WS2A", "WS2" ]

Links

ENSG00000187098 ∙ NCBI:4286 ∙ OMIM:156845 ∙ HGNC:7105 ∙ Uniprot:O75030 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Waardenburg syndrome type 2A (Strong), mode of inheritance: AD
• ocular albinism with congenital sensorineural hearing loss (Definitive), mode of inheritance: AD
• Tietz syndrome (Definitive), mode of inheritance: AD
• Waardenburg syndrome type 2A (Definitive), mode of inheritance: AD
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (Strong), mode of inheritance: AR
• renal cell carcinoma (Moderate), mode of inheritance: AD
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (Strong), mode of inheritance: AR
• Tietz syndrome (Moderate), mode of inheritance: AD
• Waardenburg syndrome type 2 (Supportive), mode of inheritance: AD
• Waardenburg-Shah syndrome (Supportive), mode of inheritance: AD
• Tietz syndrome (Supportive), mode of inheritance: AD
• melanoma, cutaneous malignant, susceptibility to, 8 (Moderate), mode of inheritance: AD
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (Strong), mode of inheritance: AR
• melanoma, cutaneous malignant, susceptibility to, 8 (Strong), mode of inheritance: AD
• Waardenburg syndrome type 2A (Strong), mode of inheritance: AD
• Waardenburg syndrome type 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Waardenburg syndrome, type 2A; Tietz albinism-deafness syndrome; Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD); Melanoma, cutaneous malignant, susceptibility to, 8; Renal cell carcinoma with or without malignant melanoma	AD	Audiologic/Otolaryngologic; Oncologic	For Waardenburg syndrome, type 2A, Tietz albinism-deafness syndrome, and COMMAD, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; For Melanoma, cutaneous malignant, susceptibility to and Renal cell carcinoma with or without malignant melanoma, awareness may allow preventive measures, surveillance, and early diagnosis and treatment of disease	Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Musculoskeletal; Ophthalmologic; Oncologic	13985019; 5006208; 331943; 666627; 7951321; 7874167; 7702105; 7573125; 8589691; 9158138; 10851256; 18510545; 20024939; 22012259; 22080950; 23167872; 23414473; 23774529; 23802662; 24638154; 24767713; 27889061
Digenic inheritance (with TYR) has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MITF gene.

• Waardenburg syndrome type 2A (16 variants)
• not provided (10 variants)
• Tietz syndrome;Waardenburg syndrome type 2A;Melanoma, cutaneous malignant, susceptibility to, 8 (5 variants)
• Rare genetic deafness (4 variants)
• Waardenburg syndrome type 2A;Tietz syndrome;Melanoma, cutaneous malignant, susceptibility to, 8 (3 variants)
• Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (2 variants)
• Melanoma, cutaneous malignant, susceptibility to, 8;Tietz syndrome;Waardenburg syndrome type 2A (2 variants)
• Waardenburg syndrome type 1 (1 variants)
• Heterochromia iridis;Poliosis;Prelingual sensorineural hearing impairment (1 variants)
• Melanoma, cutaneous malignant, susceptibility to, 8;Waardenburg syndrome type 2A;Tietz syndrome (1 variants)
• Hearing impairment (1 variants)
• Nonsyndromic genetic hearing loss (1 variants)
• Waardenburg syndrome (1 variants)
• Tietz syndrome (1 variants)
• Ear malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MITF gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1	1	6	76	2	86
missense	1	9	235	5	1	251
nonsense	13	6	1			20
start loss		1	1			2
frameshift	12	3	1			16
inframe indel	1		1			2
splice donor/acceptor (+/-2bp)	2	8				10
splice region		1	13	32		46
non coding		1	59	75	42	177
Total	30	29	304	156	45

Variants in MITF

This is a list of pathogenic ClinVar variants found in the MITF region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-69739569-C-T		not specified	Likely benign (Aug 15, 2023)
3-69739657-G-T		not specified	Uncertain significance (Jun 02, 2016)
3-69739661-A-G		MITF-related disorder	Uncertain significance (Jan 03, 2024)
3-69739769-C-G			Likely benign (Jun 21, 2018)
3-69739945-C-A			Likely benign (Jun 21, 2018)
3-69763693-G-T			Benign/Likely benign (Jul 01, 2024)
3-69763752-C-T			Benign (Jun 21, 2018)
3-69763864-C-T			Likely benign (Aug 01, 2023)
3-69763889-C-G		Tietz syndrome	Uncertain significance (May 09, 2019)
3-69763911-A-G		MITF-related disorder	Uncertain significance (Mar 19, 2023)
3-69763917-T-C		not specified • Hereditary cancer-predisposing syndrome	Likely benign (Jul 01, 2024)
3-69763927-G-A		not specified • Hereditary cancer-predisposing syndrome • MITF-related disorder	Conflicting classifications of pathogenicity (Apr 15, 2021)
3-69763939-GA-G			Uncertain significance (Jul 09, 2020)
3-69794494-C-T		MITF-related disorder	Uncertain significance (Apr 05, 2024)
3-69794509-T-C		MITF-related disorder	Uncertain significance (Aug 18, 2023)
3-69866298-C-T		not specified	Likely benign (Jun 29, 2015)
3-69866302-T-C		MITF-related disorder	Likely benign (Dec 09, 2019)
3-69866343-A-G		MITF-related disorder	Uncertain significance (Oct 30, 2023)
3-69866345-C-T		not specified	Uncertain significance (Oct 18, 2016)
3-69879094-T-C		not specified	Likely benign (Aug 15, 2023)
3-69879137-T-G		MITF-related disorder	Uncertain significance (Aug 18, 2023)
3-69879140-C-T		MITF-related disorder	Likely benign (Jun 06, 2023)
3-69879143-C-T		not specified	Likely benign (Nov 24, 2014)
3-69879170-G-A		MITF-related disorder	Likely benign (Jun 02, 2022)
3-69879170-G-T		MITF-related disorder	Likely benign (Mar 27, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MITF	protein_coding	protein_coding	ENST00000352241	10	228903

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.981	0.0188	125704	0	4	125708	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.47	243	317	0.768	0.0000187	3439
Missense in Polyphen		66	119.39	0.5528		1263
Synonymous	0.359	116	121	0.958	0.00000772	977
Loss of Function	4.38	4	29.8	0.134	0.00000191	289

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.000109	0.000109
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium. {ECO:0000269|PubMed:10587587, ECO:0000269|PubMed:22647378, ECO:0000269|PubMed:27889061, ECO:0000269|PubMed:9647758}.
• Disease: DISEASE: Waardenburg syndrome 2A (WS2A) [MIM:193510]: WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1. {ECO:0000269|PubMed:28236341, ECO:0000269|PubMed:8589691}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Waardenburg syndrome 2, with ocular albinism, autosomal recessive (WS2-OA) [MIM:103470]: A disorder characterized by the association of features typical of Waardenburg syndrome type 2 with ocular albinism. Patients manifest reduced visual acuity, albinotic fundus, deafness, hypomelanosis. {ECO:0000269|PubMed:9647758}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tietz albinism-deafness syndrome (TADS) [MIM:103500]: An autosomal dominant disorder characterized by generalized hypopigmentation and congenital, bilateral, profound sensorineural deafness. {ECO:0000269|PubMed:10851256}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Melanoma, cutaneous malignant 8 (CMM8) [MIM:614456]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:22012259, ECO:0000269|PubMed:22080950}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD) [MIM:617306]: An autosomal recessive syndrome characterized by severe microphthalmia, profound congenital sensorineural hearing loss, lack of pigment in the hair, skin, and eyes, macrocephaly, facial dysmorphism, and osteopetrosis. {ECO:0000269|PubMed:27889061}. Note=The disease is caused by mutations affecting the gene represented in this entry. An allelic combination involving at least one dominant-negative mutation, inherited in a recessive manner, represents the underlying molecular mechanism leading to COMMAD syndrome. {ECO:0000269|PubMed:27889061}.; DISEASE: Note=Variations affecting this gene are associated with susceptibility to pheochromocytomas and paragangliomas, rare neural crest-derived tumors with an approximate incidence of 1:300,000/year. {ECO:0000269|PubMed:27680874}.
• Pathway: Melanoma - Homo sapiens (human);Mitophagy - animal - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Melanogenesis - Homo sapiens (human);RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Neural Crest Differentiation;Kit receptor signaling pathway;Prostaglandin Synthesis and Regulation;melanocyte development and pigmentation pathway;SUMOylation of transcription factors;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;Metabolism of proteins;KitReceptor;SUMOylation;Regulation of nuclear beta catenin signaling and target gene transcription;Signaling mediated by p38-alpha and p38-beta;Signaling events mediated by Stem cell factor receptor (c-Kit);Regulation of retinoblastoma protein;IL6-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.423

Intolerance Scores

• loftool: 0.203
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.73

Haploinsufficiency Scores

• pHI: 0.851
• hipred: Y
• hipred_score: 0.825
• ghis: 0.562

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.944

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mitf
• Phenotype: vision/eye phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; pigmentation phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; growth/size/body region phenotype; hematopoietic system phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: mitfa
• Affected structure: iridophore
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;transcription, DNA-templated;regulation of transcription, DNA-templated;positive regulation of gene expression;osteoclast differentiation;melanocyte differentiation;negative regulation of cell migration;regulation of cell population proliferation;camera-type eye development;canonical Wnt signaling pathway involved in negative regulation of apoptotic process;cell fate commitment;regulation of osteoclast differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;bone remodeling;protein-containing complex assembly;positive regulation of DNA-templated transcription, initiation;regulation of RNA biosynthetic process
• Cellular component: nucleus;nucleoplasm;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;protein binding;protein dimerization activity;E-box binding