ENTPD1

protein-coding

ectonucleoside triphosphate diphosphohydrolase 1, the group of CD molecules|Ectonucleoside triphosphate diphosphohydrolase family

Gene summary

The protein encoded by this gene is a plasma membrane protein that hydrolyzes extracellular ATP and ADP to AMP. Inhibition of this protein's activity may confer anticancer benefits. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

Previous symbols:

CD39

MANE transcript

NM_001776.6

Inheritance

ClinVar variants

P:20U:112B:60

Top phenotype

Spastic paraplegia 64, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr10:95,711,779-95,877,266

External References & Databases

Ensembl (ENSG00000138185)

Transcript & Mutation Effects

hg38 • Region Span ~165.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 64STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: PanelApp Australia

hereditary spastic paraplegia 64STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 64MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Ambry Genetics

hereditary spastic paraplegia 64DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Baylor College of Medicine Research Center

complex hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015150

Submitter: ClinGen

*ENTPD1* (Ectonucleoside triphosphate diphosphohydrolase-1, also known as CD39), hydrolyzes extracellular ATP and ADP to AMP, and plays an important role in regulating adenosine levels. *ENTPD1* was first reported in relation to autosomal recessive complex hereditary spastic paraplegia in 2014 (Novarino et al., PMID: 24482476). A study describing a cohort of 27 individuals with homozygous variants in *ENTPD1* identified common features of gait impairment, progressive spastic paraplegia and developmental delay/intellectual disability, with variable additional features (Calame et al. 2022, PMID: 35471564). Seven variants (missense, nonsense, frameshift) that have been reported in 12 affected individuals in 6 publications (PMIDs: 24482476, 29691679, 30652007, 33771085, 35758610, 35471564) are included in this curation. Additional evidence has been reported in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. In summary, there is definitive evidence to support the relationship between *ENTPD1* and autosomal recessive complex hereditary spastic paraplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on April 6, 2023 (SOP 9).

hereditary spastic paraplegia 64LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Illumina

hereditary spastic paraplegia 64LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Illumina

neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

hereditary spastic paraplegia 64SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014303

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spastic paraplegia 64, autosomal recessiveAR

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 24482476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ENTPD1 variants in ClinVar

9 Conditions Cataloged

Hereditary spastic paraplegia 64Total: 162

Inborn genetic diseasesTotal: 58

not providedTotal: 36

Hereditary spastic paraplegiaTotal: 19

ENTPD1-related disorderTotal: 7

not specifiedTotal: 3

PolymicrogyriaTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001776.6. 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			5 clinvar	51 clinvar	1 clinvar	57
missense	1 clinvar	1 clinvar	102 clinvar	7 clinvar	1 clinvar	112
nonsense	8 clinvar	1 clinvar	1 clinvar			10
start loss						0
frameshift	2 clinvar	3 clinvar				5
splice donor/acceptor (+/-2bp)		4 clinvar	4 clinvar			8
Total	11	9	112	58	2	192

Highest pathogenic variant AF is 0.000013137497

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001776.6	RefSeq	NP_001767.3	10	MANE Select
ENST00000371205.5	Ensembl	ENSP00000360248.4	10	MANE Select
NM_001098175.2	RefSeq	NP_001091645.1	10	Standard
NM_001164178.1	RefSeq	NP_001157650.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)
Pyrimidine metabolism
Nucleobase catabolism

Biological Process

cell adhesion
blood coagulation
nucleobase-containing small molecule catabolic process

Molecular Function

protein binding
ATP binding
nucleoside-diphosphatase activity
nucleoside-triphosphatase activity
dATP phosphohydrolase activity

Cellular Component

plasma membrane
integral component of plasma membrane
membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371207
Coding exons: 10
Length: 165488
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.832	226	264	0.856	0.0000130	3467
Missense (PolyPhen)		68	98.714	0.68886		1301
Synonymous	1.09	89	103	0.863	0.00000573	967
Loss of Function	3.02	8	24.0	0.334	0.00000104	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: In the nervous system, could hydrolyze ATP and other nucleotides to regulate purinergic neurotransmission. Could also be implicated in the prevention of platelet aggregation by hydrolyzing platelet-activating ADP to AMP. Hydrolyzes ATP and ADP equally well. {ECO:0000269|PubMed:8955160}.;
Disease: DISEASE: Spastic paraplegia 64, autosomal recessive (SPG64) [MIM:615683]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:24482476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.239

Intolerance Scores

LoFtool: 0.568
RVIS EVS: -0.34
RVIS percentile EVS: 30.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.189

Gene Damage Prediction

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