PNPLA1

protein-coding

patatin like phospholipase domain containing 1, the group of Patatin like phospholipase domain containing

Gene summary

The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

MANE transcript

NM_001374623.1

Inheritance

ClinVar variants

P:55U:110B:57

Top phenotype

Ichthyosis, congenital, autosomal recessive 10

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr6:36,243,203-36,313,955

External References & Databases

Ensembl (ENSG00000180316)

Transcript & Mutation Effects

hg38 • Region Span ~70.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive congenital ichthyosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014011

Submitter: Genomics England PanelApp

congenital non-bullous ichthyosiform erythrodermaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019306

Submitter: Orphanet

autosomal recessive congenital ichthyosis 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014011

Submitter: Ambry Genetics

autosomal recessive congenital ichthyosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014011

Submitter: G2P

autosomal recessive congenital ichthyosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014011

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive congenital ichthyosis 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014011

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Ichthyosis, congenital, autosomal recessive 10AR

Manifestation: Dermatologic

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: 22246504; 24344921; 26691440; 28403545

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PNPLA1 variants in ClinVar

12 Conditions Cataloged

Autosomal recessive congenital ichthyosis 10Total: 101

not providedTotal: 99

Inborn genetic diseasesTotal: 81

Congenital ichthyosiform erythrodermaTotal: 16

Lamellar ichthyosisTotal: 13

not specifiedTotal: 12

PNPLA1-related disorderTotal: 11

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001374623.1. 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	34 clinvar	2 clinvar	39
missense	11 clinvar	22 clinvar	105 clinvar	15 clinvar	5 clinvar	158
nonsense	2 clinvar	5 clinvar	1 clinvar	1 clinvar		9
start loss						0
frameshift	4 clinvar	5 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar				6
Total	18	37	110	50	7	222

Highest pathogenic variant AF is 0.00007893637

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001374623.1	RefSeq	NP_001361552.1	9	MANE Select
ENST00000636260.2	Ensembl	ENSP00000490785.2	9	MANE Select
NM_001145716.2	RefSeq	NP_001139188.1	7	Standard
NM_001145717.1	RefSeq	NP_001139189.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

triglyceride catabolic process
lipid homeostasis

Molecular Function

triglyceride lipase activity

Cellular Component

cytoplasm
lipid droplet
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394571
Coding exons: 8
Length: 65393
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.734	283	320	0.884	0.0000189	3395
Missense (PolyPhen)		88	114.93	0.76565		1123
Synonymous	-0.815	153	141	1.09	0.00000947	1142
Loss of Function	2.47	10	22.7	0.441	0.00000130	237

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Lipid hydrolase. Important in the formation of the epidermal lipid barrier. Plays a role in glycerophospholipid metabolism. {ECO:0000269|PubMed:22246504}.;

Intolerance Scores

LoFtool: 0.745
RVIS EVS: 1.27
RVIS percentile EVS: 93.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0685

Gene Damage Prediction

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