MANF

mesencephalic astrocyte derived neurotrophic factor

Basic information

Region (hg38): 3:51385291-51389397

Previous symbols: [ "ARMET" ]

Links

ENSG00000145050 ∙ NCBI:7873 ∙ OMIM:601916 ∙ HGNC:15461 ∙ Uniprot:P55145 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Diabetes, deafness, developmental delay, and short stature syndrome	AR	Audiologic/Otolaryngologic; Endocrine	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve early-onset diabetes mellitus, and awareness may allow early identification and management	Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Neurologic	26077850; 33500254; 34815294

ClinVar

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

• not_specified (26 variants)
• MANF-related_disorder (3 variants)
• Diabetes,_deafness,_developmental_delay,_and_short_stature_syndrome (3 variants)
• Cerebro-costo-mandibular_syndrome (2 variants)
• not_provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MANF gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006010.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1	1	2
missense			27			27
nonsense		1				1
start loss						0
frameshift	1					1
splice donor/acceptor (+/-2bp)		1	3			4
Total	1	2	30	1	1

Highest pathogenic variant AF is 9.2076453e-7

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MANF	protein_coding	protein_coding	ENST00000528157	4	4351

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		124583	0	13	124596	0.0000522

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.672	66	83.3	0.793	0.00000437	1173
Missense in Polyphen		21	42.875	0.48979		531
Synonymous	0.351	28	30.5	0.919	0.00000153	349
Loss of Function	0.714	5	7.04	0.710	3.71e-7	107

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000585	0.0000585
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000645	0.0000556
Finnish	0.000232	0.000232
European (Non-Finnish)	0.0000285	0.0000266
Middle Eastern	0.0000645	0.0000556
South Asian	0.0000684	0.0000654
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain (PubMed:12794311). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (By similarity). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (PubMed:18561914, PubMed:22637475, PubMed:29497057). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475). Following secretion by the ER/SR, directly binds to 3-O- sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (PubMed:29497057). Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions (PubMed:29497057). {ECO:0000250|UniProtKB:P0C5H9, ECO:0000269|PubMed:12794311, ECO:0000269|PubMed:18561914, ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:29497057}.
• Pathway: Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Hemostasis (Consensus)

Recessive Scores

• pRec: 0.135

Intolerance Scores

• loftool: 0.303
• rvis_EVS: -0.01
• rvis_percentile_EVS: 52.85

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.114

Gene Damage Prediction

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

Zebrafish Information Network

• Gene name: manf
• Affected structure: ventral thalamus
• Phenotype tag: abnormal
• Phenotype quality: has fewer parts of type

Gene ontology

• Biological process: platelet degranulation;response to unfolded protein;regulation of signaling receptor activity;neuron projection development;dopaminergic neuron differentiation;regulation of response to endoplasmic reticulum stress
• Cellular component: extracellular region;extracellular space;nucleus;endoplasmic reticulum;endoplasmic reticulum lumen;cytosol;sarcoplasmic reticulum lumen
• Molecular function: RNA binding;growth factor activity;lipid binding