GREM1
protein-codinggremlin 1, DAN family BMP antagonist, the group of DAN family
Gene summary
This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. In mouse, this protein has been shown to relay the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge during limb bud outgrowth. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]
- CKTSF1B1
- CRAC1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018188
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0042486
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011023
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011023
Submitter: ClinGen
GREM1 was first reported in relation to autosomal dominant Hereditary mixed polyposis syndrome (HMPS) in 2012 (Jaeger et al., PMID: 22561515), after extensive genomic characterization of 6 Ashkenazi previously described families with HMPS (PMID: 9024286, 10092300, 12696020, 18084292). HMPS describes an autosomal dominantly inherited large-bowel disease characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer. Four variants including the Ashkenazi variant leading to partial or complete duplication of GREM1 regulatory regions or coding sequences have been reported in 10 probands in 9 publications (PMIDs: 9024286, 10092300, 12696020, 18084292, 21128281, 22561515, 24586997, 26493165, 29804199) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached (PMIDs: 25992589, 26947005, 28242209, 27984123). Most described patients (14 probands) are carriers of the Ashkenazi founder variant, a 40kb duplication upstream of GREM1 (SCG5-GREM1 dup) (PMID: 22561515). This gene-disease association is also supported by experimental evidence (4 points). The mechanism of pathogenicity is known to be overexpression, which was confirmed in two publications that showed increased GREM1 expression in the normal epithelium of HMPS patients compared with the controls (PMID: 22561515, 26493165). This gene-disease association is also supported by an animal model, showing that GREM1 overexpression recapitulates the HMPS phenotype in the colon and knockout reduces polyp burden and size (PMID: 25419707). In summary, GREM1 is definitively associated with autosomal dominant Hereditary mixed polyposis syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0011023
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Oncologic
Intervention: Oncologic
Rationale: Individuals are at risk of colonic neoplasms including adenomas and colorectal carcinomas (with polyps detected by 18 years of age), and awareness may allow surveillance and prompt treatment, which may be beneficial
Comments: The condition has been reported as associated with a duplication including the 3' end of the SCG5 gene upstream of GREM1
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GREM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013372.7. 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 | 158 | 1 | 159 | |||
| missense | 229 | 3 | 1 | 233 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 229 | 161 | 2 | 392 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_037504.1 | 1 | MANE Select | |
| Ensembl | ENSP00000498748.1 | 1 | MANE Select | |
| RefSeq | NP_001178251.1 | 2 | Standard | |
| RefSeq | NP_001178252.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lung fibrosis
- Canonical and Non-Canonical TGF-B signaling
- BMP receptor signaling
Biological Process
- cell morphogenesis
- branching involved in ureteric bud morphogenesis
- cell migration involved in sprouting angiogenesis
- positive regulation of receptor internalization
- positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation
Molecular Function
- cytokine activity
- protein binding
- morphogen activity
- transmembrane receptor protein tyrosine kinase activator activity
- BMP binding
Cellular Component
- extracellular space
- cell surface
- collagen-containing extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300177
- Coding exons
- 1
- Length
- 16696
- Individuals with no LoFs
- 125704
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125705
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.55 | 66 | 112 | 0.589 | 0.00000631 | 1190 |
| Missense (PolyPhen) | 11 | 36.079 | 0.30489 | 374 | ||
| Synonymous | 0.269 | 43 | 45.3 | 0.949 | 0.00000245 | 372 |
| Loss of Function | 1.85 | 1 | 5.80 | 0.173 | 2.89e-7 | 64 |
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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner (By similarity). Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro) (PubMed:27036124). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed (By similarity). {ECO:0000250|UniProtKB:O35793, ECO:0000250|UniProtKB:O70326, ECO:0000269|PubMed:27036124}.;
- Disease
- DISEASE: Polyposis syndrome, mixed hereditary 1 (HMPS1) [MIM:601228]: A disease characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Patients can develop polyps of multiple and mixed morphologies, including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas and colorectal carcinoma in the absence of any identifiable extra-colonic features. {ECO:0000269|PubMed:22561515}. Note=The disease is caused by mutations affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (PubMed:22561515). {ECO:0000269|PubMed:22561515}.;
Recessive Scores
- pRec
- 0.559
Intolerance Scores
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 62.74
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.415
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |