LTBP4

latent transforming growth factor beta binding protein 4, the group of Latent transforming growth factor beta binding proteins

Basic information

Region (hg38): 19:40592882-40629818

Links

ENSG00000090006 ∙ NCBI:8425 ∙ OMIM:604710 ∙ HGNC:6717 ∙ Uniprot:Q8N2S1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Strong), mode of inheritance: AR
• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Strong), mode of inheritance: AR
• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Strong), mode of inheritance: AR
• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Strong), mode of inheritance: AR
• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cutis laxa with severe pulmonary, gastrointestinal, and urinary abnormalities	AR	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	Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Pulmonary	19836010

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LTBP4 gene.

• not provided (644 variants)
• Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (115 variants)
• not specified (86 variants)
• Inborn genetic diseases (66 variants)
• LTBP4-related condition (5 variants)
• Cutis laxa (1 variants)
• Cutis Laxa Syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LTBP4 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			38	100	10	148
missense			323	11	11	345
nonsense	8	3				11
start loss			1			1
frameshift	5	3	1		1	10
inframe indel			4			4
splice donor/acceptor (+/-2bp)		7	1			8
splice region			12	16	3	31
non coding	1		31	87	58	177
Total	14	13	399	198	80

Highest pathogenic variant AF is 0.0000197

Variants in LTBP4

This is a list of pathogenic ClinVar variants found in the LTBP4 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-40592965-C-T			Benign (Jun 19, 2018)
19-40593167-T-C			Uncertain significance (Jan 08, 2018)
19-40593174-C-T		not specified	Likely benign (Nov 07, 2017)
19-40593175-G-A			Uncertain significance (Feb 23, 2023)
19-40593199-C-T		not specified	Likely benign (Dec 19, 2023)
19-40596970-C-T			Benign (Jun 19, 2018)
19-40597342-G-A		not specified	Benign/Likely benign (Dec 31, 2018)
19-40597348-C-A		LTBP4-related disorder	Benign (Feb 19, 2020)
19-40597390-C-T		LTBP4-related disorder	Likely benign (Oct 17, 2023)
19-40597416-A-G			Likely benign (Jan 20, 2019)
19-40598907-AATC-A			Likely benign (Jul 21, 2020)
19-40598954-G-T			Benign (Jun 23, 2018)
19-40599071-C-T			Benign (Jun 26, 2018)
19-40599178-T-C			Likely benign (Oct 03, 2023)
19-40599184-C-G			Likely benign (Nov 24, 2023)
19-40599197-C-T			Uncertain significance (Dec 17, 2023)
19-40599198-G-A			Likely benign (Aug 07, 2023)
19-40599205-T-C		not specified	Uncertain significance (Feb 17, 2022)
19-40599248-C-T		Inborn genetic diseases	Uncertain significance (Dec 09, 2023)
19-40599249-A-C			Likely benign (Mar 07, 2023)
19-40599251-C-T			Uncertain significance (Nov 27, 2019)
19-40599346-G-A			Likely benign (Aug 03, 2018)
19-40599400-A-G		Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies	Uncertain significance (Feb 02, 2022)
19-40599401-G-A		Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies	Pathogenic (Nov 20, 2019)
19-40599404-C-G			Likely benign (Aug 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LTBP4	protein_coding	protein_coding	ENST00000308370	34	36937

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.499	0.501	514	124210	6	124730	0.936

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.35	837	1.05e+3	0.796	0.0000665	10249
Missense in Polyphen		321	444.92	0.72148		4442
Synonymous	1.21	407	439	0.927	0.0000289	3365
Loss of Function	6.65	19	85.3	0.223	0.00000447	897

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	2.00	1.90
Ashkenazi Jewish	1.00	0.951
East Asian	1.00	0.976
Finnish	1.00	0.950
European (Non-Finnish)	1.00	0.925
Middle Eastern	1.00	0.976
South Asian	1.00	0.963
Other	1.00	0.937

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency- associated peptide (LAP), which is the regulatory chain of TGF- beta, and regulates integrin-dependent activation of TGF-beta. {ECO:0000250|UniProtKB:Q14766}.
• Disease: DISEASE: Urban-Rifkin-Davis syndrome (URDS) [MIM:613177]: A syndrome characterized by disrupted pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial and dermal development. Clinical features include cutis laxa, mild cardiovascular lesions, respiratory distress with cystic and atelectatic changes in the lungs, and diverticulosis, tortuosity and stenosis at various levels of the intestinal tract. Craniofacial features include microretrognathia, flat midface, receding forehead and wide fontanelles. {ECO:0000269|PubMed:19836010}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Duchenne muscular dystrophy (DMD) [MIM:310200]: Most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment. {ECO:0000269|PubMed:23440719, ECO:0000269|PubMed:25641372}. Note=The gene represented in this entry may act as a disease modifier. DMD patients homozygous for the IAAM haplotype consisting of Ile-194, Ala-787, Ala-820 and Met-1141 remain ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype consisting of Val-194, Thr-787, Thr-820 and Thr-1141. This may be due to increased binding to TGFB1, resulting in TGFB1 sequestration in the extracellular matrix and reduced TGFB1 signaling which has been linked to improved muscle function and regeneration. {ECO:0000269|PubMed:23440719}.
• Pathway: Extracellular matrix organization;Molecules associated with elastic fibres;Elastic fibre formation (Consensus)

Recessive Scores

• pRec: 0.123

Haploinsufficiency Scores

• pHI: 0.199
• hipred: Y
• hipred_score: 0.640
• ghis: 0.592

Essentials

• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 0.880

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ltbp4
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; digestive/alimentary phenotype; immune system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: regulation of cell growth;protein folding;transforming growth factor beta receptor signaling pathway;multicellular organism development;regulation of transforming growth factor beta receptor signaling pathway;regulation of proteolysis;growth hormone secretion;regulation of cell differentiation
• Cellular component: extracellular region;extracellular space;extracellular matrix;collagen-containing extracellular matrix
• Molecular function: transforming growth factor beta-activated receptor activity;integrin binding;extracellular matrix structural constituent;calcium ion binding;protein binding;glycosaminoglycan binding;transforming growth factor beta binding