GeneBe

FANCL

protein-coding

FA complementation group L, the group of PHD finger proteins|FA core complex|FA complementation groups

Gene summary

This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

Previous symbols:
  • PHF9

MANE transcript

NM_018062.4

Inheritance

AR

ClinVar variants

P:129U:278B:157

Top phenotype

Fanconi anemia, complementation group L

gnomAD constraint

pLI —, LoF o/e 1.2

Max pathogenic AF

—

Genomic locus

chr2:58,159,243-58,241,410

External References & Databases

Ensembl (ENSG00000115392)NCBI Gene (55120)OMIM (608111)HGNC:20748GenCCUniProt (Q9NW38)AlphaFoldClinVar (FANCL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~82.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group LDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: Natera

Fanconi anemia complementation group LDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: G2P

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia complementation group LSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: PanelApp Australia

Fanconi anemia complementation group LDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: ClinGen

FANCL is one of the 23 Fanconi anemia (FA) or FA-like genes known to cause autosomal recessive FA, which is a group of rare genetic disorders characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FANCL gene encodes a ubiquitin ligase that was first reported in 2003 to be a member of the Fanconi Anemia Complex (Meetei et al. PMID: 12973351). Various types of variants (e.g. in-frame indel, frameshift, insertion, putative synonymous, etc.) that have been reported in multiple unrelated probands in publications (PMID:12973351,19405097,25754594,31513304). A putative synonymous c.1107G>A, p.Lys369= (NM_001114636.1 ) variant was demonstrated to induce aberrant splicing and was suggested to be a founder mutation in the South Asian population (PMID: 31513304). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is FANCL protein loss of function. This gene-disease relationship is further supported by FANCL-deficient patient cell lines, rescue cell culture model, protein interaction and expression studies. In summary, FANCL is definitively associated with autosomal recessive FA complementation group L. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Fanconi anemia complementation group LSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Fanconi anemia complementation group LSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013566

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group LAR

Manifestation: Audiologic/Otolaryngologic; Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic

Rationale: 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

Refs: 12973351; 20301575; 22720145; 25754594Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCL variants in ClinVar

14 Conditions Cataloged
Fanconi anemiaTotal: 660
Fanconi anemia complementation group LTotal: 192
not providedTotal: 88
not specifiedTotal: 56
Inborn genetic diseasesTotal: 50
FANCL-related disorderTotal: 20
FANCL-related disordersTotal: 7
Fanconi anemia complementation group ATotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018062.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
3
clinvar
142
clinvar
1
clinvar
 147
missense
267
clinvar
12
clinvar
2
clinvar
 281
nonsense
15
clinvar
19
clinvar
 34
start loss
2
clinvar
4
clinvar
 6
frameshift
22
clinvar
35
clinvar
4
clinvar
 61
splice donor/acceptor (+/-2bp)
31
clinvar
4
clinvar
 35
Total40892781543564

Highest pathogenic variant AF is 0.00054359954

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 160 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_018062.4RefSeqNP_060532.214MANE Select
ENST00000233741.9EnsemblENSP00000233741.514MANE Select
NM_001114636.2RefSeqNP_001108108.114Standard
NM_001374615.1RefSeqNP_001361544.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Fanconi anemia pathway - Homo sapiens (human)
  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • Fanconi Anemia Pathway
  • DNA Repair
  • Fanconi anemia pathway

Biological Process

  • DNA repair
  • protein monoubiquitination
  • cellular response to DNA damage stimulus
  • gamete generation
  • interstrand cross-link repair

Molecular Function

  • ubiquitin-protein transferase activity
  • protein binding
  • ubiquitin protein ligase binding
  • metal ion binding
  • ubiquitin protein ligase activity

Cellular Component

  • nuclear envelope
  • nucleoplasm
  • cytoplasm
  • nuclear body
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000402135
Coding exons
14
Length
82130
Individuals with no LoFs
125654
Homozygous LoFs
0
Heterozygous LoFs
94
Defined
125748
p
0.000374
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-1.312511991.260.000009432494
Missense (PolyPhen)4046.1810.86616582
Synonymous-0.5987366.81.090.00000323684
Loss of Function-0.9343125.91.200.00000117318

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000690.00069rare
Ashkenazi Jewish0.000500.00050rare
East Asian0.000160.00016rare
Finnish00.0absent
European (Non-Finnish)0.000340.00034rare
South Asian0.000420.00042rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway (PubMed:12973351, PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:24389026). Also mediates monoubiquitination of FANCI (PubMed:19589784). May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth. {ECO:0000269|PubMed:12973351, ECO:0000269|PubMed:16916645, ECO:0000269|PubMed:17938197, ECO:0000269|PubMed:19111657, ECO:0000269|PubMed:19589784, ECO:0000269|PubMed:24389026}.;
Disease
DISEASE: Fanconi anemia complementation group L (FANCL) [MIM:614083]: 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. {ECO:0000269|PubMed:12973351}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.284

Intolerance Scores

LoFtool
0.985
RVIS EVS
-0.29
RVIS percentile EVS
33.2

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.875

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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