• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TGFBR1 (HGNC:11772) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
transforming growth factor beta receptor 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
MSSE, ESS1
Alias symbols
ALK-5, ACVRLK4, ALK5, TBRI, TBR-i
%HI
1.85(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.85(Read more about gnomAD pLI score)
LOEUF
0.38(Read more about gnomAD LOEUF score)
Cytoband
9q22.33
Genomic Coordinates
GRCh37/hg19: chr9:101867395-101916474 NCBI Ensembl UCSC
GRCh38/hg38: chr9:99103647-99154192 NCBI Ensembl UCSC
MANE Select Transcript
NM_004612.4 ENST00000374994.9 (Read more about MANE Select)
Function
Transmembrane serine/threonine kinase forming with the TGF- beta type II serine/threonine kinase receptor, TGFBR2, the non- promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healin... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-35571
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
02/13/2024

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • multiple self-healing squamous epitheliomas (MSSE) Monarch
HI Evidence:
  • PUBMED: 21358634
    Goudie et al. (2011): 11 mutations identified amongst 18 different families (22 families total tested) with multiple self-healing squamous epitheliomas (MSSE), including 3 nonsense (p.Arg414X, p.Trp242X and p.Arg80X), 4 frameshift mutations (p.Asn45LysfsX30, p.Pro327GlnfsX8, p.Pro327GlnfsX8 and p.Leu354AsnfsX4) and one splice variant in intron 4 (c.806−2A>C) predicting to result in loss of function. The rest are missense.
  • PUBMED: 29706644
    Fujiwara (2018) reported a novel splice donor site variant in TGFBR1 gene (c.973+1G>A; NG_007461.1), which was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain in a British familial case of MSSE. Ex vivo splicing and functional assays showed The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site and produced an out of frame transcript. It is concluded that truncating variants in STK domain induce MSSE.
  • PUBMED: 33256177
    Goudie (2020) reported a cohort of MSSE patients with one new nonsense (p.Trp475X) and one new splice mutation (c.98-1G>A) in addition to the mutations reported in 2011 (Goudie et al., 2011. PMID: 21358634). The c.122G > A p.(Arg80X) variant has been found in three independently ascertained patients from New Zealand, Switzerland, and the UK. The frameshift variant c.980delC p. (Pro327GlnfsX8) variant has been found in three Scottish families and the frameshift variant c.1059_1062del 6 ACTGinsCAATAA (p.Leu354AsnfsX4) variant has been found in two families in Scotland (Osunsade L et al., 2012; Goudie DR et al., 2011; Debroy Kidambi A et al., 2017. Muller C et al., 2016; irisomboonwong KE et al., 2018; Shukur Z et all, 2016. Feldmeyer L et al., 2016).
  • PUBMED: 25525159
    Xiong et al (2015) identified three nonsense and one frameshift variants after they scored over 650,000 variants using a computational model. These four variants were considered to be pathogenic for multiple self-healing squamous epitheliomas (MSSE) based on the records in HGMD.
HI Evidence Comments:
The haploinsufficiency rating here is based on the multiple self-healing squamous epithelioma (MSSE) phenotype. Per OMIM, "individuals with multiple self-healing squamous epithelioma (MSSE) develop multiple invasive skin tumors that undergo spontaneous regression leaving pitted scars. Age at onset is highly variable, ranging from 8 to 62 years. The disorder shows autosomal dominant inheritance, and most affected families have originated from western Scotland (Bose et al., 2006). MSSE has been considered to be a variety of multiple keratoacanthoma (Biskind et al., 1957; Haydey et al., 1980)." Truncating variants of the entire gene or missense variants in the receptor domain of TGFBR1 cause multiple self-healing squamous epithelioma (MSSE; OMIM 132800) through haploinsufficiency mechanism. One of the reported stop-gain variants, p.R414*, has a MAF of 0.0002% in gnomAD. Recent studies proposed a second linked locus playing a role in the development of MSSE (PMIDs: 38112607, 33256177, 24747516). Therefore, a haploinsufficiency score of 3 was assigned. Of note, variants in TGFBR1 are also associated with Loeys-Dietz syndrome (LDS); the mutational mechanisms associated with this syndrome are incompletely understood, though evidence is emerging to suggest that mutations associated with this phenotype are gain-of-function mutations. See the Loeys-Dietz GeneReviews (under "Abnormal Gene Product" in the "Molecular Genetics" section for a full discussion) (http://www.ncbi.nlm.nih.gov/books/NBK1133/). Over 120 variants have been identified in TGBFR1 with the majority being missense and more rarely, nonsense, splice site and small deletions. Two nonsense variants, c.428T>A (p.L143*) and c.672G>A (p.W224*), have been described by Strong et al. (2021) and Olfson et al. (2015) (PMIDs: 34355836, 26332594) in patients with LDS, but not MSSE. Fujiwara et al (2019) in PMID: 33693090 used ex vivo minigene splicing arrays demonstrated that different but similar splicing variants can produce different transcripts. The out-of-frame transcript result from the splicing variant associated with MSSE. The in-frame transcript results from the splicing variant associated with LDS. These findings supporting the mechanism of haploinsufficiency in MSSE. In addition, Rasnic et al (2020) in PMID: 32778766 reported a stop-gain variant, TGFBR1 c.238C>T (p.R80*), in one skin cancer and one breast cancer patient after analyzing the UK-Biobank data containing ~70,000 cancer patients and ~430,000 cancer free individuals. The author defined this variant as cancer-exclusive ultra-rare variant (detected at least in 2 cancer patients and no healthy individuals). At this time, the relationship between variants in this gene and cancer risk is unclear.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
20813212 Breckpot et al. (2010): A report of a 17-year-old boy with pubertas tarda, a bifid uvula, camptodactyly and facial dysmorphic features, which the authors describe as suggestive of Loeys Dietz syndrome. No evidence of any arterial tortuosity or other cardiac abnormality was seen on echocardiography or abdominal ultrasound at 17 years of age. Mutation analysis of TGFBR1 and TGFBR2 was normal, but the individual was found to have a 120 kb deletion on chromosome 22q13.31q13.32, inherited from an unaffected parent, and a de novo 14.6 Mb duplication on chromosome 9q22.32q31.3, comprising TGFBR1 (along with 56 other genes) (PMID:20813212). Though it is possible that the duplication of TGFBR1 could be contributing to the patient's features, this cannot be definitively stated.

Genomic View

Select assembly: (NC_000009.11) (NC_000009.12)