PDE3A

protein-coding

phosphodiesterase 3A, the group of Phosphodiesterases

Gene summary

This gene encodes a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase (cGI-PDE) family. cGI-PDE enzymes hydrolyze both cAMP and cGMP, and play critical roles in many cellular processes by regulating the amplitude and duration of intracellular cyclic nucleotide signals. The encoded protein mediates platelet aggregation and also plays important roles in cardiovascular function by regulating vascular smooth muscle contraction and relaxation. Inhibitors of the encoded protein may be effective in treating congestive heart failure. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

MANE transcript

NM_000921.5

Inheritance

ClinVar variants

P:11U:221B:94

Top phenotype

Hypertension with brachydactyly syndrome

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr12:20,368,537-20,688,583

External References & Databases

Ensembl (ENSG00000172572)

Transcript & Mutation Effects

hg38 • Region Span ~320.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

brachydactyly-arterial hypertension syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007211

Submitter: Labcorp Genetics (formerly Invitae)

brachydactyly-arterial hypertension syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007211

Submitter: PanelApp Australia

brachydactyly-arterial hypertension syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007211

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hypertension with brachydactyly syndromeAD

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: Individuals have been described as suffering from death by stroke by age 50 when untreated, and awareness may allow early management of hypertension, which has been described as having onset in childhood

Refs: 4774535; 9415685; 25961942

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDE3A variants in ClinVar

8 Conditions Cataloged

not providedTotal: 162

Inborn genetic diseasesTotal: 145

not specifiedTotal: 42

PDE3A-related disorderTotal: 30

Brachydactyly-arterial hypertension syndromeTotal: 26

Prostate cancerTotal: 1

VATER associationTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000921.5. 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			2 clinvar	57 clinvar	11 clinvar	70
missense	7 clinvar	4 clinvar	210 clinvar	23 clinvar	2 clinvar	246
nonsense			6 clinvar			6
start loss						0
frameshift			1 clinvar	1 clinvar		2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	7	4	221	81	13	326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000921.5	RefSeq	NP_000912.3	16	MANE Select
ENST00000359062.4	Ensembl	ENSP00000351957.3	16	MANE Select
NM_001244683.2	RefSeq	NP_001231612.1	15	Standard
NM_001378407.1	RefSeq	NP_001365336.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

cAMP signaling pathway - Homo sapiens (human)
Renin secretion - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
cGMP-PKG signaling pathway - Homo sapiens (human)
Morphine addiction - Homo sapiens (human)

Biological Process

oocyte maturation
lipid metabolic process
G protein-coupled receptor signaling pathway
cAMP-mediated signaling
cGMP-mediated signaling

Molecular Function

3',5'-cyclic-AMP phosphodiesterase activity
cGMP-inhibited cyclic-nucleotide phosphodiesterase activity
protein binding
metal ion binding
3',5'-cyclic-GMP phosphodiesterase activity

Cellular Component

cytosol
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359062
Coding exons: 16
Length: 315137
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.592	586	628	0.933	0.0000313	7379
Missense (PolyPhen)		121	202.59	0.59725		2297
Synonymous	-2.00	296	255	1.16	0.0000135	2322
Loss of Function	4.13	15	44.8	0.335	0.00000207	555

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00084	0.00080	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00060	rare
Finnish	0.000098	0.000092	rare
European (Non-Finnish)	0.00024	0.00023	rare
South Asian	0.00026	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cyclic nucleotide phosphodiesterase with a dual- specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. {ECO:0000250|UniProtKB:Q9Z0X4}.;
Disease: DISEASE: Hypertension and brachydactyly syndrome (HTNB) [MIM:112410]: A syndrome characterized by brachydactyly type E, severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, and altered baroreflex blood pressure regulation. It results in death from stroke before age 50 years when untreated. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. {ECO:0000269|PubMed:25961942}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.399
RVIS EVS: -1.1
RVIS percentile EVS: 6.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.956

Gene Damage Prediction

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