P4HTM

prolyl 4-hydroxylase, transmembrane

Basic information

Region (hg38): 3:48989889-49007153

Links

ENSG00000178467 ∙ NCBI:54681 ∙ OMIM:614584 ∙ HGNC:28858 ∙ Uniprot:Q9NXG6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (Moderate), mode of inheritance: AR
• hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities	AR	Pulmonary	Individuals have been described with respiratory difficulties, including bradypnea, hypoventilation, recurrent pneunomia, and sleep apnea (often requiring nighttime BiPAP), and awareness may allow early management of pulmonary issues	Craniofacial; Neurologic; Ophthalmologic; Pulmonary	25078763; 30940925

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the P4HTM gene.

• not provided (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the P4HTM 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				8		8
missense		1	46	3		50
nonsense	2					2
start loss						0
frameshift	2	1	3			6
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			1			1
Total	4	2	50	11	0

Highest pathogenic variant AF is 0.0000131

Variants in P4HTM

This is a list of pathogenic ClinVar variants found in the P4HTM region.

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

Position	Type	Phenotype	Significance	ClinVar
3-48990284-C-T		Inborn genetic diseases	Uncertain significance (Dec 04, 2024)
3-48990326-T-C		Inborn genetic diseases	Uncertain significance (Nov 13, 2024)
3-48990339-A-C		Inborn genetic diseases	Uncertain significance (Feb 10, 2022)
3-48990339-A-G		Inborn genetic diseases	Uncertain significance (Apr 09, 2024)
3-48990355-G-A			Likely benign (Jul 01, 2024)
3-48990365-G-C		Inborn genetic diseases	Uncertain significance (Sep 26, 2023)
3-48990384-A-G		Inborn genetic diseases	Uncertain significance (Jan 16, 2025)
3-48990393-T-G		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
3-48990395-C-T		Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
3-48990426-C-T		Inborn genetic diseases	Uncertain significance (Oct 16, 2024)
3-48990438-TC-T			Pathogenic (Jul 05, 2022)
3-48990457-C-A			Uncertain significance (Apr 12, 2023)
3-48990457-C-G		Inborn genetic diseases	Uncertain significance (Apr 10, 2023)
3-48990458-G-C		Inborn genetic diseases	Uncertain significance (Apr 10, 2023)
3-48990488-C-G		Inborn genetic diseases	Uncertain significance (Mar 17, 2023)
3-48990538-G-GC		Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities • Intellectual disability	Uncertain significance (Dec 31, 2017)
3-48990914-G-A		Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities	Uncertain significance (-)
3-49001473-C-G			Uncertain significance (Jul 19, 2022)
3-49001483-A-C		Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities • Intellectual disability	Uncertain significance (Dec 31, 2017)
3-49001489-C-T		Inborn genetic diseases	Uncertain significance (Jan 18, 2022)
3-49001510-G-A		Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities	Uncertain significance (Feb 01, 2022)
3-49001535-G-A			Likely benign (Jan 01, 2024)
3-49001552-G-C		Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities	Uncertain significance (Jan 17, 2022)
3-49001557-A-C		Inborn genetic diseases	Uncertain significance (Dec 14, 2023)
3-49001568-C-G		Inborn genetic diseases	Uncertain significance (Mar 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
P4HTM	protein_coding	protein_coding	ENST00000343546	9	17269

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.92e-9	0.795	125714	0	34	125748	0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.54	253	332	0.762	0.0000188	3632
Missense in Polyphen		88	135.43	0.64979		1482
Synonymous	0.233	134	137	0.975	0.00000763	1165
Loss of Function	1.54	17	25.4	0.670	0.00000117	263

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000423	0.000421
Ashkenazi Jewish	0.00	0.00
East Asian	0.000171	0.000163
Finnish	0.0000935	0.0000924
European (Non-Finnish)	0.000101	0.0000967
Middle Eastern	0.000171	0.000163
South Asian	0.000265	0.000261
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the post-translational formation of 4- hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. {ECO:0000269|PubMed:17726031}.

Recessive Scores

• pRec: 0.153

Intolerance Scores

• loftool: 0.215
• rvis_EVS: -0.09
• rvis_percentile_EVS: 46.92

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.563
• ghis: 0.545

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.644

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: P4htm
• Phenotype: homeostasis/metabolism phenotype; hematopoietic system phenotype; vision/eye phenotype; renal/urinary system phenotype

Zebrafish Information Network

• Gene name: p4htm
• Affected structure: lens capsule
• Phenotype tag: abnormal
• Phenotype quality: broken

Gene ontology

• Biological process: peptidyl-proline hydroxylation to 4-hydroxy-L-proline;regulation of erythrocyte differentiation;oxidation-reduction process
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;integral component of membrane
• Molecular function: procollagen-proline 4-dioxygenase activity;iron ion binding;calcium ion binding;2-oxoglutarate-dependent dioxygenase activity;L-ascorbic acid binding