GDF15

protein-coding

growth differentiation factor 15, the group of Transforming growth factor beta superfamily|MicroRNA protein coding host genes

Gene summary

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]

MANE transcript

NM_004864.4

Inheritance

—

ClinVar variants

U:53B:6

Top phenotype

Hyperemesis gravidarum, susceptibility to

gnomAD constraint

pLI —, LoF o/e 1.24

Max pathogenic AF

—

Genomic locus

chr19:18,374,731-18,389,176

External References & Databases

Ensembl (ENSG00000130513)

Transcript & Mutation Effects

hg38 • Region Span ~14.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GDF15 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 52

not providedTotal: 4

Hyperemesis gravidarum, susceptibility toTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004864.4. 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			2 clinvar		2 clinvar	4
missense			50 clinvar	3 clinvar	1 clinvar	54
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	53	3	3	59

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004864.4	RefSeq	NP_004855.2	2	MANE Select
ENST00000252809.3	Ensembl	ENSP00000252809.3	2	MANE Select
ENST00000595973.3	Ensembl	ENSP00000470531.3	2	Standard
ENST00000597765.2	Ensembl	ENSP00000469819.2	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EMT transition in Colorectal Cancer
p73 transcription factor network
Validated transcriptional targets of TAp63 isoforms
Direct p53 effectors

Biological Process

activation of MAPK activity
reduction of food intake in response to dietary excess
signal transduction
transforming growth factor beta receptor signaling pathway
cell-cell signaling

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
protein binding
growth factor activity
protein homodimerization activity

Cellular Component

extracellular region
extracellular space
nucleus
cytoplasm
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252809
Coding exons: 2
Length: 14446
Individuals with no LoFs: 125690
Homozygous LoFs: 1
Heterozygous LoFs: 26
Defined: 125717
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.292	189	201	0.942	0.0000118	1893
Missense (PolyPhen)		37	44.297	0.83527		473
Synonymous	-0.240	102	99.0	1.03	0.00000592	706
Loss of Function	-0.597	9	7.26	1.24	3.99e-7	65

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00034	0.00031	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000058	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00012	rare
South Asian	0.00023	0.00020	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099, PubMed:23468844, PubMed:29046435). Binds to its receptor, GFRAL, and activates GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem (PubMed:28953886, PubMed:28846097, PubMed:28846098, PubMed:28846099). It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which contitutes part of the 'emergency circuit' that shapes feeding responses to stressful conditions (PubMed:28953886). On hepatocytes, inhibits growth hormone signaling (By similarity). {ECO:0000250|UniProtKB:Q9Z0J7, ECO:0000269|PubMed:23468844, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846098, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:29046435}.;
Disease: DISEASE: Note=Plasma levels are increased in children with concomitant heart disease and failure to thrive but not in children with heart disease and normal body weight. {ECO:0000269|PubMed:28572090}.;

Recessive Scores

pRec: 0.360

Intolerance Scores

LoFtool: 0.353
RVIS EVS: 0.73
RVIS percentile EVS: 86.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.570

Gene Damage Prediction

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