PLD3

protein-coding

phospholipase D family member 3, the group of Phospholipases|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2014]

MANE transcript

NM_012268.4

Inheritance

AD, AR

ClinVar variants

U:128B:55

Top phenotype

Spinocerebellar ataxia 46

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr19:40,348,456-40,389,472

External References & Databases

Ensembl (ENSG00000105223)

Transcript & Mutation Effects

hg38 • Region Span ~41.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia 46SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033481

Submitter: Orphanet

spinocerebellar ataxia 46MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033481

Submitter: PanelApp Australia

leukodystrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019046

Submitter: PanelApp Australia

spinocerebellar ataxia 46LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033481

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 46AD

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: 8595484; 29053796

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLD3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 143

not specifiedTotal: 84

PLD3-related disorderTotal: 11

Spinocerebellar ataxia 46Total: 7

Alzheimer disease 19Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012268.4. 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			3 clinvar	36 clinvar	4 clinvar	43
missense			118 clinvar	14 clinvar	1 clinvar	133
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	128	50	5	183

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 141 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012268.4	RefSeq	NP_036400.2	11	MANE Select
ENST00000409735.9	Ensembl	ENSP00000386938.3	11	MANE Select
NM_001031696.4	RefSeq	NP_001026866.1	11	Standard
NM_001291311.2	RefSeq	NP_001278240.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ether lipid metabolism - Homo sapiens (human)
Glycerophospholipid metabolism - Homo sapiens (human)
metabolism of anandamide an endogenous cannabinoid
Metabolism of lipids
Role of phospholipids in phagocytosis

Biological Process

lipid catabolic process

Molecular Function

phospholipase D activity
protein binding
N-acylphosphatidylethanolamine-specific phospholipase D activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409587
Coding exons: 11
Length: 31984
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125747
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.999	262	312	0.841	0.0000198	3159
Missense (PolyPhen)		60	76.984	0.77939		814
Synonymous	0.936	119	133	0.897	0.00000852	1016
Loss of Function	2.44	12	25.2	0.476	0.00000121	257

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in APP processing. {ECO:0000305|PubMed:24336208}.;
Disease: DISEASE: Spinocerebellar ataxia 46 (SCA46) [MIM:617770]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA46 is a slowly progressive, autosomal dominant form with onset in adulthood. {ECO:0000269|PubMed:29053796}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Genetic variants in PLD3 have been suggested to be associated with an increased risk for Alzheimer disease (PubMed:24336208, PubMed:25832409). Further studies, however, did not support PLD3 involvement in this disease (PubMed:25832408, PubMed:25832411, PubMed:25832413, PubMed:25832410, PubMed:26411346). {ECO:0000269|PubMed:24336208, ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409, ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411, ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346}.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.668
RVIS EVS: -0.51
RVIS percentile EVS: 21.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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