SLX4

SLX4 structure-specific endonuclease subunit, the group of BTB domain containing|FA complementation groups

Basic information

Region (hg38): 16:3581181-3611606

Previous symbols: [ "BTBD12" ]

Links

ENSG00000188827 ∙ NCBI:84464 ∙ OMIM:613278 ∙ HGNC:23845 ∙ Uniprot:Q8IY92 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Fanconi anemia complementation group P (Definitive), mode of inheritance: AR
• Fanconi anemia (Supportive), mode of inheritance: AR
• Fanconi anemia complementation group P (Strong), mode of inheritance: AR
• familial ovarian cancer (No Known Disease Relationship), mode of inheritance: AD
• hereditary breast carcinoma (Refuted Evidence), mode of inheritance: AD
• Fanconi anemia complementation group P (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Fanconi anemia, complementation group P	AR	Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic	Specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count); HSCT can be curative, but solid tumor risk may remain; Surveillance for complications such as bone marrow failure is recommended; Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management	Audiologic/Otolaryngologic; Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal	21240275; 21240277; 20301575

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLX4 gene.

• Fanconi anemia (65 variants)
• not provided (4 variants)
• Fanconi anemia complementation group P (3 variants)
• Fanconi anemia complementation group A (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLX4 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			17	512	14	543
missense			1079	26	13	1118
nonsense	29	12	3			44
start loss						0
frameshift	41	13	1			55
inframe indel			31	1		32
splice donor/acceptor (+/-2bp)		11				11
splice region			27	19	1	47
non coding			45	91	44	180
Total	70	36	1176	630	71

Highest pathogenic variant AF is 0.0000197

Variants in SLX4

This is a list of pathogenic ClinVar variants found in the SLX4 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-3581192-C-G		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581247-C-T		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581295-C-T		Fanconi anemia complementation group P	Uncertain significance (Jan 12, 2018)
16-3581301-T-C		Fanconi anemia complementation group P	Likely benign (Jan 13, 2018)
16-3581307-T-C		Fanconi anemia complementation group P	Likely benign (Jan 13, 2018)
16-3581320-T-C		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581338-T-C		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581358-G-A		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581385-G-A		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581398-T-C		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581455-G-A		Fanconi anemia complementation group P	Uncertain significance (Jan 12, 2018)
16-3581460-G-A		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581471-T-C		Fanconi anemia complementation group P	Uncertain significance (Jan 12, 2018)
16-3581531-C-G		Fanconi anemia complementation group P	Uncertain significance (Jan 12, 2018)
16-3581535-C-T		Fanconi anemia complementation group P	Benign (Jan 13, 2018)
16-3581621-A-G		Fanconi anemia complementation group P	Benign (Jan 13, 2018)
16-3581684-A-G		Fanconi anemia complementation group P	Likely benign (Jan 13, 2018)
16-3581687-C-T		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581690-T-C		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581764-C-T		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581787-G-A		Fanconi anemia complementation group P	Benign (Jan 12, 2018)
16-3581849-C-A		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581873-T-A		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3581968-G-A		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)
16-3582031-C-T		Fanconi anemia complementation group P	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLX4	protein_coding	protein_coding	ENST00000294008	14	30418

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.57e-22	0.846	125591	0	157	125748	0.000624

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.88	1224	1.05e+3	1.16	0.0000702	11861
Missense in Polyphen		296	270.99	1.0923		3358
Synonymous	-4.09	577	465	1.24	0.0000356	3821
Loss of Function	2.41	45	66.2	0.680	0.00000369	767

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000651	0.000650
Ashkenazi Jewish	0.00	0.00
East Asian	0.00132	0.00131
Finnish	0.000372	0.000370
European (Non-Finnish)	0.000709	0.000695
Middle Eastern	0.00132	0.00131
South Asian	0.000852	0.000817
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases. Has several distinct roles in protecting genome stability by resolving diverse forms of deleterious DNA structures originating from replication and recombination intermediates and from DNA damage. Component of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable, nicked duplex products. Interacts with the structure- specific ERCC4-ERCC1 endonuclease and promotes the cleavage of bubble structures. Interacts with the structure-specific MUS81- EME1 endonuclease and promotes the cleavage of 3'-flap and replication fork-like structures. SLX4 is required for recovery from alkylation-induced DNA damage and is involved in the resolution of DNA double-strand breaks. {ECO:0000269|PubMed:19595721, ECO:0000269|PubMed:19595722, ECO:0000269|PubMed:19596235, ECO:0000269|PubMed:19596236}.
• Disease: DISEASE: Fanconi anemia complementation group P (FANCP) [MIM:613951]: A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Some individuals affected by Fanconi anemia of complementation group P have skeletal anomalies. {ECO:0000269|PubMed:21240275, ECO:0000269|PubMed:21240277}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);Fanconi Anemia Pathway;DNA Repair;DNA Double-Strand Break Repair;Homology Directed Repair;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Intolerance Scores

• rvis_EVS: 1.17
• rvis_percentile_EVS: 92.73

Haploinsufficiency Scores

• pHI: 0.0621
• hipred: Y
• hipred_score: 0.568
• ghis: 0.547

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: N
• gene_indispensability_score: 0.114

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slx4
• Phenotype: growth/size/body region phenotype; endocrine/exocrine gland phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; immune system phenotype; skeleton 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); reproductive system phenotype; 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); hematopoietic system 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); limbs/digits/tail phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: slx4
• Affected structure: intrahepatic bile duct
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: meiotic DNA double-strand break processing;resolution of meiotic recombination intermediates;double-strand break repair via homologous recombination;DNA replication;DNA repair;nucleotide-excision repair;DNA double-strand break processing involved in repair via single-strand annealing;interstrand cross-link repair;positive regulation of catalytic activity;telomeric D-loop disassembly;response to intra-S DNA damage checkpoint signaling;t-circle formation;negative regulation of telomere maintenance via telomere lengthening;positive regulation of t-circle formation
• Cellular component: chromosome, telomeric region;nuclear chromosome, telomeric region;nuclear chromatin;nucleoplasm;cytosol;cell junction;Slx1-Slx4 complex;Holliday junction resolvase complex;ERCC4-ERCC1 complex
• Molecular function: endodeoxyribonuclease activity;protein binding;enzyme activator activity;crossover junction endodeoxyribonuclease activity;5'-flap endonuclease activity;3'-flap endonuclease activity