GREM1

gremlin 1, DAN family BMP antagonist, the group of DAN family

Basic information

Region (hg38): 15:32718004-32745106

Previous symbols: [ "CKTSF1B1", "CRAC1" ]

Links

ENSG00000166923 ∙ NCBI:26585 ∙ OMIM:603054 ∙ HGNC:2001 ∙ Uniprot:O60565 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary mixed polyposis syndrome (Supportive), mode of inheritance: AD
• polyposis syndrome, hereditary mixed, 1 (Strong), mode of inheritance: AD
• hereditary mixed polyposis syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Polyposis syndrome, mixed hereditary 1	AD	Oncologic	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	Oncologic	22561515; 26493165 ; 26947005
The condition has been reported as associated with a duplication including the 3' end of the SCG5 gene upstream of GREM1

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GREM1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GREM1 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	93	1	95
missense			120			120
nonsense						0
start loss						0
frameshift						0
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				10	59	69
Total	0	0	122	103	60

Variants in GREM1

This is a list of pathogenic ClinVar variants found in the GREM1 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-32718041-A-T		not specified	Likely benign (Aug 15, 2023)
15-32718052-G-A		not specified	Benign (Aug 15, 2023)
15-32718078-G-A		not specified	Likely benign (Aug 15, 2023)
15-32718087-C-G		not specified	Likely benign (Aug 15, 2023)
15-32718091-G-A		not specified	Likely benign (Aug 15, 2023)
15-32718099-C-G		not specified	Likely benign (Aug 15, 2023)
15-32718114-G-A		not specified	Likely benign (Aug 15, 2023)
15-32718140-C-G		not specified	Likely benign (Aug 15, 2023)
15-32718170-G-C		not specified	Likely benign (Aug 15, 2023)
15-32718211-G-A			Benign (Jul 06, 2018)
15-32718282-T-C			Benign (Jul 14, 2018)
15-32718535-G-A			Benign (Jul 06, 2018)
15-32718926-G-A			Benign (Jul 05, 2018)
15-32719440-A-G			Benign (Jul 06, 2018)
15-32719496-G-C			Benign (Jul 06, 2018)
15-32719539-TC-T			Benign (Jul 05, 2018)
15-32719650-G-T			Benign (Jul 05, 2018)
15-32719675-T-G		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
15-32720031-T-C			Benign (Jun 14, 2019)
15-32720217-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
15-32720301-A-G		Familial colorectal cancer	Benign (Sep 20, 2022)
15-32720437-G-A			Benign (Jul 15, 2018)
15-32720879-A-G			Benign (Jul 05, 2018)
15-32721018-T-A			Benign (Jul 06, 2018)
15-32721569-G-C			Benign (Jul 05, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GREM1	protein_coding	protein_coding	ENST00000300177	1	16696

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.474	0.504	125704	0	1	125705	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.55	66	112	0.589	0.00000631	1190
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000880
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Lung fibrosis;Canonical and Non-Canonical TGF-B signaling;BMP receptor signaling (Consensus)

Recessive Scores

• pRec: 0.559

Intolerance Scores

• rvis_EVS: 0.13
• rvis_percentile_EVS: 62.74

Haploinsufficiency Scores

• pHI: 0.810
• hipred: Y
• hipred_score: 0.736
• ghis: 0.541

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.415

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Grem1
• 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); embryo phenotype; respiratory system phenotype; renal/urinary system phenotype; skeleton 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); limbs/digits/tail phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• 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;mesenchymal to epithelial transition involved in metanephros morphogenesis;apoptotic process;signal transduction;activation of transmembrane receptor protein tyrosine kinase activity;cell-cell signaling;positive regulation of cell population proliferation;proximal/distal pattern formation;regulation of epithelial to mesenchymal transition;collagen fibril organization;negative regulation of cell growth;embryonic limb morphogenesis;negative regulation of bone mineralization;negative regulation of BMP signaling pathway;negative regulation of chondrocyte differentiation;regulation of stress-activated MAPK cascade;negative regulation of osteoblast proliferation;negative regulation of apoptotic process;negative regulation of osteoblast differentiation;positive regulation of angiogenesis;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;negative regulation of bone remodeling;determination of dorsal identity;positive regulation of NF-kappaB transcription factor activity;regulation of focal adhesion assembly;positive regulation of telomerase activity;limb development;negative regulation of pathway-restricted SMAD protein phosphorylation;ureteric bud formation;positive regulation of protein tyrosine kinase activity;signal transduction by p53 class mediator;negative regulation of monocyte chemotaxis;negative regulation of canonical Wnt signaling pathway;positive regulation of branching involved in ureteric bud morphogenesis;negative regulation of branching involved in ureteric bud morphogenesis;negative regulation of osteoclast proliferation;positive regulation of peptidyl-tyrosine autophosphorylation;negative regulation of bone trabecula formation;negative regulation of bone mineralization involved in bone maturation;positive regulation of NIK/NF-kappaB signaling;positive regulation of signaling receptor activity;positive regulation of cardiac muscle cell differentiation
• Cellular component: extracellular space;cell surface;collagen-containing extracellular matrix
• Molecular function: cytokine activity;protein binding;morphogen activity;transmembrane receptor protein tyrosine kinase activator activity;BMP binding;protein homodimerization activity;vascular endothelial growth factor receptor 2 binding;receptor ligand activity