P4HTM

protein-coding

prolyl 4-hydroxylase, transmembrane

Gene summary

The product of this gene belongs to the family of prolyl 4-hydroxylases. This protein is a prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia. It plays a role in adaptation to hypoxia and may be related to cellular oxygen sensing. Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_177939.3

Inheritance

ClinVar variants

P:14U:90B:26

Top phenotype

Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr3:48,989,889-49,007,153

External References & Databases

Ensembl (ENSG00000178467)

Transcript & Mutation Effects

hg38 • Region Span ~17.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032780

Submitter: Labcorp Genetics (formerly Invitae)

hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032780

Submitter: G2P

hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032780

Submitter: PanelApp Australia

hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032780

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesAR

Manifestation: Craniofacial; Neurologic; Ophthalmologic; Pulmonary

Intervention: Pulmonary

Rationale: 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

Refs: 25078763; 30940925

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to P4HTM variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 76

not providedTotal: 37

not specifiedTotal: 21

Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalitiesTotal: 19

P4HTM-related disorderTotal: 11

Intellectual disabilityTotal: 3

P4HTM-related disordersTotal: 2

Poirier-Bienvenu neurodevelopmental syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177939.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	21 clinvar		22
missense	1 clinvar	5 clinvar	83 clinvar	5 clinvar		94
nonsense	3 clinvar		1 clinvar			4
start loss						0
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		2 clinvar	3 clinvar			5
Total	5	9	90	26	0	130

Highest pathogenic variant AF is 0.00003717435

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_177939.3	RefSeq	NP_808808.1	9	MANE Select
ENST00000383729.9	Ensembl	ENSP00000373235.4	9	MANE Select
NM_177938.2	RefSeq	NP_808807.2	9	Standard
ENST00000343546.8	Ensembl	ENSP00000341422.4	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
p4htm	Danio rerio	Structure: lens capsule Quality: broken abnormal

Gene / Model

Organism

Observed Phenotype

p4htm

Danio rerio

Structure: lens capsule

Quality: broken

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

peptidyl-proline hydroxylation to 4-hydroxy-L-proline
regulation of erythrocyte differentiation
oxidation-reduction process

Molecular Function

procollagen-proline 4-dioxygenase activity
iron ion binding
calcium ion binding
2-oxoglutarate-dependent dioxygenase activity
L-ascorbic acid binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343546
Coding exons: 9
Length: 17269
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.54	253	332	0.762	0.0000188	3632
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.644

Gene Damage Prediction

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