PTHLH

parathyroid hormone like hormone, the group of Receptor ligands|Neuropeptides

Basic information

Region (hg38): 12:27958084-27972733

Links

ENSG00000087494 ∙ NCBI:5744 ∙ OMIM:168470 ∙ HGNC:9607 ∙ Uniprot:P12272 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• brachydactyly type E2 (Definitive), mode of inheritance: AD
• brachydactyly type E2 (Strong), mode of inheritance: AD
• brachydactyly type E (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brachydactyly, type E2	AD	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	Dental; Musculoskeletal	20170896

ClinVar

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

• not provided (5 variants)
• Brachydactyly type E2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PTHLH 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	14		15
missense	1		37	1		39
nonsense	3					3
start loss		3				3
frameshift	2		1			3
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			1			1
non coding				5	4	9
Total	6	3	40	20	4

Highest pathogenic variant AF is 0.00000657

Variants in PTHLH

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

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

Position	Type	Phenotype	Significance	ClinVar
12-27958386-C-CA			Benign (Aug 15, 2019)
12-27958559-T-C		Brachydactyly type E2	Pathogenic (Mar 12, 2010)
12-27958568-C-T			Uncertain significance (Aug 06, 2023)
12-27958570-T-G			Uncertain significance (Aug 10, 2023)
12-27963124-C-T			Likely benign (Feb 07, 2019)
12-27963129-G-A			Likely benign (Oct 16, 2018)
12-27963178-C-T			Likely benign (Oct 16, 2018)
12-27963333-A-C			Likely benign (Jun 18, 2023)
12-27963346-A-G		Inborn genetic diseases	Likely pathogenic (Jun 22, 2017)
12-27963366-G-A		Inborn genetic diseases	Uncertain significance (Aug 02, 2023)
12-27963369-G-A			Uncertain significance (May 25, 2022)
12-27963373-T-C			Uncertain significance (Oct 25, 2022)
12-27963387-A-G			Uncertain significance (Nov 14, 2022)
12-27963390-T-TA		PTHLH-related disorder	Uncertain significance (Jan 19, 2023)
12-27963393-T-G			Uncertain significance (Jun 11, 2021)
12-27963397-C-T		PTHLH-related disorder	Uncertain significance (Dec 31, 2023)
12-27963406-C-T			Uncertain significance (Dec 03, 2022)
12-27963407-ACT-A		Brachydactyly type E2	Likely pathogenic (-)
12-27963414-G-C			Uncertain significance (Jun 18, 2021)
12-27963425-G-C			Likely benign (Jul 26, 2023)
12-27963439-A-G			Uncertain significance (Aug 27, 2023)
12-27963441-C-T			Uncertain significance (Mar 11, 2022)
12-27963442-G-C			Uncertain significance (Oct 19, 2023)
12-27963450-C-T			Uncertain significance (Jan 19, 2021)
12-27963451-G-T			Likely benign (Dec 28, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PTHLH	protein_coding	protein_coding	ENST00000395872	3	14622

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.811	0.188	125736	0	1	125737	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.15	74	108	0.687	0.00000660	1124
Missense in Polyphen		26	46.106	0.56392		482
Synonymous	1.39	33	44.9	0.735	0.00000273	361
Loss of Function	2.62	1	9.88	0.101	7.77e-7	86

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)	0.00000879	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1- dependent manner through activation of Rac1. {ECO:0000250, ECO:0000269|PubMed:20637541}.
• Disease: DISEASE: Brachydactyly E2 (BDE2) [MIM:613382]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges. {ECO:0000269|PubMed:20170896}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Endoderm Differentiation;Vitamin D Receptor Pathway;Regulation of Apoptosis by Parathyroid Hormone-related Protein;Endochondral Ossification;Signaling by GPCR;Signal Transduction;G alpha (s) signalling events;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR downstream signalling;Signaling events mediated by the Hedgehog family (Consensus)

Recessive Scores

• pRec: 0.489

Intolerance Scores

• loftool: 0.239
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58

Haploinsufficiency Scores

• pHI: 0.785
• hipred: Y
• hipred_score: 0.853
• ghis: 0.475

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.804

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pthlh
• Phenotype: renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; limbs/digits/tail 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); digestive/alimentary phenotype; neoplasm; normal 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); hematopoietic system phenotype; 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); liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); 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

Zebrafish Information Network

• Gene name: pthlhb
• Affected structure: ceratohyal bone
• Phenotype tag: abnormal
• Phenotype quality: deformed

Gene ontology

• Biological process: skeletal system development;osteoblast development;G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;cell-cell signaling;female pregnancy;positive regulation of cell population proliferation;negative regulation of cell population proliferation;epidermis development;regulation of gene expression;regulation of signaling receptor activity;bone mineralization;negative regulation of chondrocyte differentiation;cAMP metabolic process;negative regulation of chondrocyte development
• Cellular component: extracellular region;extracellular space;nucleoplasm;cytoplasm;Golgi apparatus;cytosol
• Molecular function: hormone activity;peptide hormone receptor binding