PNPLA6

patatin like phospholipase domain containing 6, the group of Patatin like phospholipase domain containing

Basic information

Region (hg38): 19:7534004-7561764

Links

ENSG00000032444 ∙ NCBI:10908 ∙ OMIM:603197 ∙ HGNC:16268 ∙ Uniprot:Q8IY17 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Laurence-Moon syndrome (Supportive), mode of inheritance: AR
• cerebellar ataxia-hypogonadism syndrome (Supportive), mode of inheritance: AR
• ataxia-hypogonadism-choroidal dystrophy syndrome (Supportive), mode of inheritance: AR
• trichomegaly-retina pigmentary degeneration-dwarfism syndrome (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 39 (Supportive), mode of inheritance: AR
• ataxia-hypogonadism-choroidal dystrophy syndrome (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 39 (Strong), mode of inheritance: AR
• retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome (Definitive), mode of inheritance: AR
• PNPLA6-related spastic paraplegia with or without ataxia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Boucher-Neuhauser syndrome; Laurence-Moon syndrome; Oliver-McFarlane syndrome	AR	Endocrine	For Boucher-Neuhauser syndrome, Laurence-Moon syndrome, and Oliver-McFarlane syndrome, management related to hypogonadotropic hyponadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) may be beneficial; Related to fertility in Boucher-Neuhaser syndrome, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required; For Oliver-McFarlane syndrome, recognition of other pituitary deficiencies (such as thyroid hormone deficiency) may allow prompt diagnosis and medical management	Craniofacial; Genitourinary; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic	8053762; 18313024; 24355708; 25033069; 25480986

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PNPLA6 gene.

• Hereditary spastic paraplegia 39 (47 variants)
• not provided (9 variants)
• Ataxia-hypogonadism-choroidal dystrophy syndrome (4 variants)
• Spastic ataxia (2 variants)
• Trichomegaly-retina pigmentary degeneration-dwarfism syndrome (2 variants)
• Inborn genetic diseases (2 variants)
• Hereditary spastic paraplegia (1 variants)
• PNPLA6-related disorder (1 variants)
• Hypogonadism with anosmia (1 variants)
• Rod-cone dystrophy (1 variants)
• Laurence-Moon syndrome (1 variants)
• Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;Laurence-Moon syndrome;Ataxia-hypogonadism-choroidal dystrophy syndrome;Hereditary spastic paraplegia 39 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PNPLA6 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			21	271	4	296
missense	10	12	404	9	1	436
nonsense	15	1	1			17
start loss			1			1
frameshift	26	6	4			36
inframe indel			4			4
splice donor/acceptor (+/-2bp)	4	15	2			21
splice region			43	53	2	98
non coding			23	211	77	311
Total	55	34	460	491	82

Highest pathogenic variant AF is 0.000125

Variants in PNPLA6

This is a list of pathogenic ClinVar variants found in the PNPLA6 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-7534022-G-C		Mucolipidosis type IV	Uncertain significance (Jan 12, 2018)
19-7534137-T-C		Hereditary spastic paraplegia 39	Uncertain significance (Jan 13, 2018)
19-7534174-T-C		Mucolipidosis type IV • Hereditary spastic paraplegia 39	Benign (Mar 28, 2022)
19-7534221-C-T		Mucolipidosis type IV • Hereditary spastic paraplegia 39	Benign/Likely benign (May 17, 2018)
19-7534235-C-T		Hereditary spastic paraplegia 39	Uncertain significance (Jan 13, 2018)
19-7534329-C-T			Benign (Mar 28, 2022)
19-7534823-G-A		Hereditary spastic paraplegia 39	Uncertain significance (Jan 12, 2018)
19-7534846-A-C		Hereditary spastic paraplegia 39	Uncertain significance (Jan 12, 2018)
19-7534849-A-C		Spastic Paraplegia, Recessive • Mucolipidosis type IV • Hereditary spastic paraplegia 39	Benign/Likely benign (May 14, 2021)
19-7534892-T-C		Hereditary spastic paraplegia 39	Uncertain significance (Jan 12, 2018)
19-7534905-G-A		not specified • Hereditary spastic paraplegia 39	Conflicting classifications of pathogenicity (Jan 13, 2018)
19-7535117-A-T			Likely benign (Feb 08, 2022)
19-7535122-T-C			Benign (May 18, 2021)
19-7535552-T-C		Hereditary spastic paraplegia 39	Uncertain significance (Nov 27, 2023)
19-7535556-G-A		Hereditary spastic paraplegia 39	Likely benign (Nov 08, 2022)
19-7535557-G-A		Hereditary spastic paraplegia 39	Uncertain significance (Jan 04, 2024)
19-7535560-C-T		Hereditary spastic paraplegia 39	Uncertain significance (Jan 13, 2018)
19-7535561-C-A		Retinal dystrophy • Hereditary spastic paraplegia	Uncertain significance (Feb 19, 2019)
19-7535562-G-A		Hereditary spastic paraplegia 39	Likely benign (Jul 22, 2022)
19-7535563-CT-GG		Hereditary spastic paraplegia 39	Uncertain significance (Jul 19, 2022)
19-7535564-T-A		Hereditary spastic paraplegia 39	Uncertain significance (Mar 10, 2022)
19-7535573-G-A		Hereditary spastic paraplegia 39	Uncertain significance (Aug 10, 2023)
19-7535576-T-C		Hereditary spastic paraplegia 39	Uncertain significance (Aug 23, 2023)
19-7535588-G-C		Hereditary spastic paraplegia 39	Likely benign (Sep 07, 2022)
19-7535591-C-A		Hereditary spastic paraplegia 39	Likely benign (Dec 14, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PNPLA6	protein_coding	protein_coding	ENST00000414982	33	27761

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.94e-13	1.00	125631	0	117	125748	0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.35	529	896	0.591	0.0000669	8701
Missense in Polyphen		101	264.78	0.38146		2518
Synonymous	-0.146	401	397	1.01	0.0000307	2942
Loss of Function	4.00	33	68.8	0.480	0.00000390	725

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000509	0.000507
Ashkenazi Jewish	0.000100	0.0000992
East Asian	0.000384	0.000381
Finnish	0.000374	0.000370
European (Non-Finnish)	0.000651	0.000642
Middle Eastern	0.000384	0.000381
South Asian	0.000425	0.000425
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Its specific chemical modification by certain organophosphorus (OP) compounds leads to distal axonopathy. {ECO:0000269|PubMed:15044461, ECO:0000269|PubMed:1666291}.
• Disease: DISEASE: Spastic paraplegia 39, autosomal recessive (SPG39) [MIM:612020]: 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. SPG39 is associated with a motor axonopathy affecting upper and lower limbs and resulting in progressive wasting of distal upper and lower extremity muscles. {ECO:0000269|PubMed:18313024, ECO:0000269|PubMed:24355708}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Boucher-Neuhauser syndrome (BNHS) [MIM:215470]: An autosomal recessive disorder characterized by spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset is variable, but most patients develop 1 or more symptoms in the first decade of life. Chorioretinal dystrophy may not always be present. {ECO:0000269|PubMed:24355708, ECO:0000269|PubMed:25033069}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Laurence-Moon syndrome (LNMS) [MIM:245800]: An autosomal recessive syndrome characterized by progressive spinocerebellar degeneration, spastic paraplegia, mental retardation, hypogonadism, dwarfism, and chorioretinopathy. Trichomegaly is absent. {ECO:0000269|PubMed:25480986}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Oliver-McFarlane syndrome (OMCS) [MIM:275400]: A rare autosomal recessive, congenital syndrome characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies. It results in intellectual impairment and dwarfism, if untreated. Clinical features include hypogonadotropic hypogonadism during puberty, pigmentary retinal degeneration, ataxia, spastic paraplegia, and peripheral neuropathy. {ECO:0000269|PubMed:25480986}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Glycerophospholipid metabolism - Homo sapiens (human);Metabolism of lipids;Metabolism;Glycerophospholipid catabolism;PI Metabolism;Phospholipid metabolism (Consensus)

Recessive Scores

• pRec: 0.159

Intolerance Scores

• loftool: 0.822
• rvis_EVS: -1.14
• rvis_percentile_EVS: 6.38

Haploinsufficiency Scores

• pHI: 0.103
• hipred: Y
• hipred_score: 0.563
• ghis: 0.509

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.546

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pnpla6
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); embryo phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: pnpla6
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: phosphatidylcholine metabolic process;glycerophospholipid catabolic process
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;membrane;integral component of membrane
• Molecular function: lysophospholipase activity