MBTPS2

membrane bound transcription factor peptidase, site 2

Basic information

Region (hg38): X:21839616-21885423

Previous symbols: [ "KFSD" ]

Links

ENSG00000012174 ∙ NCBI:51360 ∙ OMIM:300294 ∙ HGNC:15455 ∙ Uniprot:O43462 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• osteogenesis imperfecta (Supportive), mode of inheritance: AD
• IFAP syndrome 1, with or without BRESHECK syndrome (Supportive), mode of inheritance: AD
• keratosis follicularis spinulosa decalvans (Supportive), mode of inheritance: AD
• mutilating palmoplantar keratoderma with periorificial keratotic plaques (Supportive), mode of inheritance: AD
• BRESEK syndrome (Supportive), mode of inheritance: XL
• keratosis follicularis spinulosa decalvans, X-linked (Limited), mode of inheritance: XL
• IFAP syndrome 1, with or without BRESHECK syndrome (Strong), mode of inheritance: XL
• Olmsted syndrome, X-linked (Limited), mode of inheritance: XL
• osteogenesis imperfecta, type 19 (Limited), mode of inheritance: XL
• IFAP syndrome 1, with or without BRESHECK syndrome (Strong), mode of inheritance: XL
• osteogenesis imperfecta, type 19 (Strong), mode of inheritance: XL
• IFAP syndrome 1, with or without BRESHECK syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Keratosis follicularis spinulosa decalvans, X-linked; IFAP syndrome 1 with or without BRESHECK syndrome; Olmsted syndrome, X-linked; Osteogenesis imperfecta, type XIX	XL	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal	1552542; 10398262; 10694306; 8745901; 18984066; 19361614; 20672378; 22105905; 24313295; 27380894

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MBTPS2 gene.

• not provided (3 variants)
• IFAP syndrome 1, with or without BRESHECK syndrome (1 variants)
• Keratosis follicularis spinulosa decalvans, X-linked (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MBTPS2 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	26	5	32
missense	3	2	57	6	4	72
nonsense						0
start loss						0
frameshift						0
inframe indel			8			8
splice donor/acceptor (+/-2bp)						0
splice region			2	2	1	5
non coding			18	12	14	44
Total	3	2	84	44	23

Variants in MBTPS2

This is a list of pathogenic ClinVar variants found in the MBTPS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-21839746-G-A			Likely benign (Apr 25, 2022)
X-21839750-C-T			Likely benign (May 21, 2023)
X-21839750-CTGGTGGTGGTGG-C			Uncertain significance (Nov 20, 2012)
X-21839750-C-CTGGTGG			Uncertain significance (May 22, 2024)
X-21839753-G-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 22, 2023)
X-21839764-G-C		MBTPS2-related disorder	Benign/Likely benign (Jan 20, 2024)
X-21839765-G-A			Uncertain significance (Jan 21, 2024)
X-21839767-G-A			Uncertain significance (Mar 14, 2022)
X-21839783-G-A			Uncertain significance (Feb 10, 2022)
X-21839788-C-T			Likely benign (Sep 27, 2023)
X-21839797-C-T			Likely benign (Nov 23, 2022)
X-21839801-G-C			Uncertain significance (Dec 01, 2022)
X-21839801-G-T			Uncertain significance (Feb 18, 2022)
X-21842842-G-C			Benign (Nov 12, 2018)
X-21843213-A-C		IFAP syndrome 1, with or without BRESHECK syndrome • Inborn genetic diseases	Uncertain significance (May 04, 2022)
X-21843213-A-G		MBTPS2-related disorder	Benign/Likely benign (Sep 01, 2023)
X-21843217-C-T			Likely benign (Aug 29, 2023)
X-21843218-G-A		Olmsted syndrome, X-linked	Uncertain significance (Feb 24, 2023)
X-21843225-G-C		Inborn genetic diseases	Likely benign (Jun 07, 2024)
X-21843239-C-T		Inborn genetic diseases	Uncertain significance (Nov 01, 2021)
X-21843269-C-T		Osteogenesis imperfecta, type 19	Uncertain significance (Jun 16, 2020)
X-21843270-G-A			Uncertain significance (May 17, 2022)
X-21843311-T-A			Benign (Jan 17, 2024)
X-21843312-A-G		Inborn genetic diseases • MBTPS2-related disorder • not specified	Benign/Likely benign (Feb 07, 2024)
X-21843316-A-G		not specified	Benign (Jan 31, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MBTPS2	protein_coding	protein_coding	ENST00000379484	11	45789

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.998	0.00248	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.09	112	194	0.577	0.0000143	3365
Missense in Polyphen		9	56.742	0.15861		962
Synonymous	0.136	69	70.4	0.979	0.00000509	1063
Loss of Function	3.89	0	17.6	0.00	0.00000125	295

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)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Intramembrane proteolysis of sterol-regulatory element- binding proteins (SREBPs) within the first transmembrane segment thereby releasing the N-terminal segment with a portion of the transmembrane segment attached. Site-2 cleavage comes after site-1 cleavage which takes place in the lumenal loop.
• Disease: DISEASE: Olmsted syndrome, X-linked (OLMSX) [MIM:300918]: A rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at all lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas. The digital constriction may progress to autoamputation of fingers and toes. {ECO:0000269|PubMed:22931912}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800]: A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration. {ECO:0000269|PubMed:20672378}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Protein processing in endoplasmic reticulum - Homo sapiens (human);Sterol Regulatory Element-Binding Proteins (SREBP) signalling;ATF6 (ATF6-alpha) activates chaperones;Metabolism of lipids;Unfolded Protein Response (UPR);Metabolism of proteins;Regulation of cholesterol biosynthesis by SREBP (SREBF);Metabolism;CREB3 factors activate genes;Transport of small molecules;Metabolism of steroids;srebp control of lipid synthesis;Assembly of active LPL and LIPC lipase complexes;Plasma lipoprotein assembly, remodeling, and clearance;Plasma lipoprotein remodeling (Consensus)

Intolerance Scores

• loftool: 0.0889
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.31

Haploinsufficiency Scores

• pHI: 0.240
• hipred: Y
• hipred_score: 0.728
• ghis: 0.678

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.843

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mbtps2

Zebrafish Information Network

• Gene name: mbtps2
• Affected structure: lipid localization
• Phenotype tag: abnormal
• Phenotype quality: disrupted

Gene ontology

• Biological process: cholesterol metabolic process;endoplasmic reticulum unfolded protein response;membrane protein intracellular domain proteolysis;response to endoplasmic reticulum stress;ATF6-mediated unfolded protein response;regulation of cholesterol biosynthetic process;positive regulation of DNA-binding transcription factor activity;bone maturation;positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
• Cellular component: Golgi membrane;cytoplasm;endoplasmic reticulum membrane;integral component of membrane
• Molecular function: metalloendopeptidase activity;metal ion binding