WDFY3

WD repeat and FYVE domain containing 3, the group of Armadillo like helical domain containing|BEACH domain containing |Zinc fingers FYVE-type|WD repeat domain containing

Basic information

Region (hg38): 4:84668765-84966690

Links

ENSG00000163625 ∙ NCBI:23001 ∙ OMIM:617485 ∙ HGNC:20751 ∙ Uniprot:Q8IZQ1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• syndromic intellectual disability (Supportive), mode of inheritance: AD
• autism spectrum disorder (Moderate), mode of inheritance: AD
• complex neurodevelopmental disorder (Moderate), mode of inheritance: AD
• syndromic intellectual disability (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly 18, primary, autosomal dominant	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	27008544

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WDFY3 gene.

• not_provided (468 variants)
• Inborn_genetic_diseases (270 variants)
• Microcephaly_18,_primary,_autosomal_dominant (78 variants)
• WDFY3-related_disorder (61 variants)
• not_specified (24 variants)
• Neurodevelopmental_delay (13 variants)
• Neurodevelopmental_disorder (8 variants)
• See_cases (5 variants)
• Prostate_cancer (3 variants)
• Autism_spectrum_disorder (2 variants)
• Esophageal_atresia/tracheoesophageal_fistula (1 variants)
• Syndromic_intellectual_disability (1 variants)
• Microcephaly (1 variants)
• . (1 variants)
• Macrocephaly-autism_syndrome (1 variants)
• Macrocephaly (1 variants)
• Intellectual_disability,_autosomal_dominant_1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WDFY3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000014991.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	39	7	51
missense	3	12	625	55	3	698
nonsense	20	16	4			40
start loss						0
frameshift	8	12	8			28
splice donor/acceptor (+/-2bp)	2	4	8			14
Total	33	44	650	94	10

Highest pathogenic variant AF is 0.000006568921

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WDFY3	protein_coding	protein_coding	ENST00000295888	65	296841

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.17e-25	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.82	1176	1.89e+3	0.623	0.000101	23100
Missense in Polyphen		183	467.77	0.39122		5820
Synonymous	-0.358	708	696	1.02	0.0000384	6866
Loss of Function	12.1	7	184	0.0380	0.0000104	2146

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000187	0.000185
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000125	0.000123
Middle Eastern	0.00	0.00
South Asian	0.0000999	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for selective macroautophagy (aggrephagy). Acts as an adapter protein by linking specific proteins destined for degradation to the core autophagic machinery members, such as the ATG5-ATG12-ATG16L E3-like ligase, SQSTM1 and LC3 (PubMed:20417604). Along with p62/SQSTM1, involved in the formation and autophagic degradation of cytoplasmic ubiquitin- containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with SQSTM1, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Important for normal brain development. Essential for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Involved in the ability of neural cells to respond to guidance cues. Required for cortical neurons to respond to the trophic effects of netrin- 1/NTN1 (By similarity). Regulates Wnt signaling through the removal of DVL3 aggregates, likely in an autophagy-dependent manner. This process may be important for the determination of brain size during embryonic development (PubMed:27008544). May regulate osteoclastogenesis by acting on the TNFSF11/RANKL - TRAF6 pathway (By similarity). After cytokinetic abscission, involved in midbody remnant degradation (PubMed:24128730). In vitro strongly binds to phosphatidylinositol 3-phosphate (PtdIns3P) (PubMed:15292400). {ECO:0000250|UniProtKB:Q6VNB8, ECO:0000269|PubMed:15292400, ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:20417604, ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:27008544}.
• Disease: DISEASE: Microcephaly 18, primary, autosomal dominant (MCPH18) [MIM:617520]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH18 affected individuals manifest microcephaly with mild to moderate intellectual disability. {ECO:0000269|PubMed:27008544}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.114

Intolerance Scores

• loftool: 0.279
• rvis_EVS: -2.82
• rvis_percentile_EVS: 0.63

Haploinsufficiency Scores

• pHI: 0.301
• hipred: Y
• hipred_score: 0.756
• ghis: 0.543

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.224

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wdfy3
• Phenotype: cellular 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); 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); normal phenotype

Gene ontology

• Biological process: multicellular organism development;aggrephagy
• Cellular component: nucleus;nuclear envelope;nucleolus;cytoplasm;autophagosome;cytosol;plasma membrane;inclusion body;PML body;extrinsic component of membrane;axon;nuclear membrane;Atg12-Atg5-Atg16 complex;perikaryon;extrinsic component of autophagosome membrane
• Molecular function: beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase activity;protein binding;1-phosphatidylinositol binding;metal ion binding