PAFAH1B1

platelet activating factor acetylhydrolase 1b regulatory subunit 1, the group of WD repeat domain containing

Basic information

Region (hg38): 17:2593183-2685615

Previous symbols: [ "MDCR", "MDS" ]

Links

ENSG00000007168 ∙ NCBI:5048 ∙ OMIM:601545 ∙ HGNC:8574 ∙ Uniprot:P43034 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lissencephaly due to LIS1 mutation (Definitive), mode of inheritance: AD
• lissencephaly due to LIS1 mutation (Strong), mode of inheritance: AD
• lissencephaly due to LIS1 mutation (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lissencephaly 1	AD	General	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	Neurologic	9063735; 9817918; 11502906; 11754098; 12621583; 17664403; 18285425; 19050731; 19667223; 20846927; 25140959

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PAFAH1B1 gene.

• Lissencephaly due to LIS1 mutation (78 variants)
• not provided (46 variants)
• not specified (1 variants)
• Intellectual disability (1 variants)
• Lissencephaly (1 variants)
• Abnormal cortical gyration (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PAFAH1B1 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			4	62	4	70
missense	16	19	92	9	3	139
nonsense	29	3	1			33
start loss	1					1
frameshift	43	4				47
inframe indel			3			3
splice donor/acceptor (+/-2bp)	11	6				17
splice region	5	5	11	18	4	43
non coding		1	12	67	28	108
Total	100	33	112	138	35

Variants in PAFAH1B1

This is a list of pathogenic ClinVar variants found in the PAFAH1B1 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-2593327-C-T			Likely benign (May 13, 2021)
17-2593443-C-T			Benign (May 24, 2021)
17-2593657-C-CGGAGCT		Lissencephaly/Subcortical Band Heterotopia	Benign (Jun 14, 2016)
17-2593754-GAGA-G		Lissencephaly/Subcortical Band Heterotopia	Uncertain significance (Jun 14, 2016)
17-2593862-C-CCCCGGG		Lissencephaly/Subcortical Band Heterotopia	Uncertain significance (Jun 14, 2016)
17-2595435-T-TTTTTC			Benign (Sep 28, 2021)
17-2595566-A-G			Benign (May 13, 2021)
17-2595599-G-T			Likely benign (May 20, 2021)
17-2597742-TTCTC-T			Benign (May 14, 2021)
17-2597781-A-AGT			Benign (May 14, 2021)
17-2597798-GTC-G			Likely benign (Aug 30, 2021)
17-2598054-A-G			Likely benign (Nov 15, 2021)
17-2613291-C-G			Likely benign (Feb 01, 2023)
17-2613518-G-T			Likely benign (May 01, 2023)
17-2613581-G-A			Benign (May 01, 2022)
17-2613678-G-GAAGC			Benign (Sep 01, 2022)
17-2613843-G-T			Benign (May 01, 2022)
17-2629165-C-G		Lissencephaly due to LIS1 mutation	Uncertain significance (Aug 05, 2021)
17-2637848-A-G			Likely benign (Jul 03, 2019)
17-2638112-TA-T		Lissencephaly/Subcortical Band Heterotopia	Uncertain significance (Jun 14, 2016)
17-2638291-G-A		Lissencephaly due to LIS1 mutation	Pathogenic (Feb 08, 2013)
17-2638307-C-T		Lissencephaly	Likely pathogenic (-)
17-2638309-A-G			Likely benign (Feb 04, 2023)
17-2638310-C-T		Lissencephaly due to LIS1 mutation • Subcortical band heterotopia • Lissencephaly • Intellectual disability	Pathogenic/Likely pathogenic (Apr 07, 2024)
17-2638321-G-GT			Uncertain significance (May 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PAFAH1B1	protein_coding	protein_coding	ENST00000397195	10	92406

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000529	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.53	81	232	0.349	0.0000131	2695
Missense in Polyphen		12	65.421	0.18343		825
Synonymous	0.911	67	77.2	0.868	0.00000413	754
Loss of Function	4.89	0	27.9	0.00	0.00000189	280

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors. Non-catalytic subunit of an acetylhydrolase complex which inactivates platelet- activating factor (PAF) by removing the acetyl group at the SN-2 position (By similarity). Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos (PubMed:22956769). {ECO:0000250|UniProtKB:P63005, ECO:0000269|PubMed:15173193, ECO:0000269|PubMed:22956769}.
• Disease: DISEASE: Lissencephaly 1 (LIS1) [MIM:607432]: A classical lissencephaly. It is characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six- layered cortex. The cortex is abnormally thick and poorly organized with 4 primitive layers. Associated with enlarged and dysmorphic ventricles and often hypoplasia of the corpus callosum. {ECO:0000269|PubMed:11163258, ECO:0000269|PubMed:11502906, ECO:0000269|PubMed:15007136, ECO:0000269|PubMed:15173193, ECO:0000269|PubMed:9063735}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Subcortical band heterotopia (SBH) [MIM:607432]: SBH is a mild brain malformation of the lissencephaly spectrum. It is characterized by bilateral and symmetric plates or bands of gray matter found in the central white matter between the cortex and cerebral ventricles, cerebral convolutions usually appearing normal. {ECO:0000269|PubMed:10441340, ECO:0000269|PubMed:14581661}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Miller-Dieker lissencephaly syndrome (MDLS) [MIM:247200]: A contiguous gene deletion syndrome of chromosome 17p13.3, characterized by classical lissencephaly and distinct facial features. Additional congenital malformations can be part of the condition. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ether lipid metabolism - Homo sapiens (human);Wnt Signaling Pathway and Pluripotency;Signal Transduction;Vesicle-mediated transport;lissencephaly gene (lis1) in neuronal migration and development;Membrane Trafficking;Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal;Amplification of signal from the kinetochores;Mitotic Spindle Checkpoint;Cell Cycle Checkpoints;RHO GTPases Activate Formins;RHO GTPase Effectors;Signaling by Rho GTPases;Regulation of PLK1 Activity at G2/M Transition;Recruitment of mitotic centrosome proteins and complexes;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;AURKA Activation by TPX2;G2/M Transition;Mitotic G2-G2/M phases;COPI-independent Golgi-to-ER retrograde traffic;Golgi-to-ER retrograde transport;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;Separation of Sister Chromatids;Mitotic Anaphase;Mitotic Metaphase and Anaphase;M Phase;Cell Cycle;Resolution of Sister Chromatid Cohesion;Cell Cycle, Mitotic;Anchoring of the basal body to the plasma membrane;Reelin signaling pathway;Lissencephaly gene (LIS1) in neuronal migration and development;Intra-Golgi and retrograde Golgi-to-ER traffic;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.506

Intolerance Scores

• loftool: 0.0704
• rvis_EVS: -0.41
• rvis_percentile_EVS: 26.23

Haploinsufficiency Scores

• pHI: 0.809
• hipred: Y
• hipred_score: 0.748
• ghis: 0.651

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.988

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pafah1b1
• Phenotype: growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; 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); 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)

Zebrafish Information Network

• Gene name: pafah1b1b
• Affected structure: pigment cell
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;establishment of mitotic spindle orientation;microtubule cytoskeleton organization;ameboidal-type cell migration;acrosome assembly;neuron migration;positive regulation of cytokine-mediated signaling pathway;microtubule-based process;nuclear migration;chemical synaptic transmission;neuroblast proliferation;learning or memory;retrograde axonal transport;adult locomotory behavior;protein secretion;regulation of G2/M transition of mitotic cell cycle;negative regulation of neuron projection development;lipid catabolic process;stem cell division;transmission of nerve impulse;corpus callosum morphogenesis;hippocampus development;layer formation in cerebral cortex;cerebral cortex neuron differentiation;cerebral cortex development;actin cytoskeleton organization;microtubule organizing center organization;osteoclast development;positive regulation of embryonic development;establishment of planar polarity of embryonic epithelium;regulation of GTPase activity;cortical microtubule organization;positive regulation of axon extension;positive regulation of mitotic cell cycle;negative regulation of JNK cascade;platelet activating factor metabolic process;vesicle transport along microtubule;brain morphogenesis;neuromuscular process controlling balance;microtubule sliding;nuclear envelope disassembly;establishment of centrosome localization;maintenance of centrosome location;auditory receptor cell development;positive regulation of dendritic spine morphogenesis;regulation of microtubule cytoskeleton organization;cochlea development;microtubule cytoskeleton organization involved in establishment of planar polarity;ciliary basal body-plasma membrane docking;regulation of microtubule motor activity
• Cellular component: astral microtubule;kinetochore;nuclear envelope;centrosome;cytosol;kinesin complex;microtubule associated complex;cytoplasmic microtubule;cell cortex;cell leading edge;motile cilium;nuclear membrane;stereocilium;neuron projection;neuronal cell body;perinuclear region of cytoplasm;extracellular exosome;central region of growth cone;axon cytoplasm
• Molecular function: phospholipase A2 activity;protein binding;microtubule binding;heparin binding;dynactin binding;protein homodimerization activity;phospholipase binding;dynein intermediate chain binding;microtubule plus-end binding;phosphoprotein binding;dynein complex binding