FANCM

FA complementation group M, the group of FA core complex|FA complementation groups|RNA helicases

Basic information

Region (hg38): 14:45135930-45200890

Previous symbols: [ "KIAA1596" ]

Links

ENSG00000187790 ∙ NCBI:57697 ∙ OMIM:609644 ∙ HGNC:23168 ∙ Uniprot:Q8IYD8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spermatogenic failure 28 (Strong), mode of inheritance: AR
• Fanconi anemia (Supportive), mode of inheritance: AR
• male infertility with azoospermia or oligozoospermia due to single gene mutation (Supportive), mode of inheritance: AD
• breast cancer (Disputed Evidence), mode of inheritance: AD
• spermatogenic failure 28 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Premature ovarian failure 15	AR	Obstetric	In Premature ovarian failure, genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency	Endocrine; Genitourinary; Obstetric	16116422; 20301575; 28837162
Individuals with FA may manifest a variety of congenital malformations, and awareness may allow prompt detection and management

ClinVar

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

• Fanconi anemia (110 variants)
• not provided (8 variants)
• Spermatogenic failure 28 (1 variants)
• FANCM-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FANCM 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			18	407	3	428
missense			1309	13	6	1328
nonsense	46	16	2			64
start loss			1			1
frameshift	67	16	4			87
inframe indel			31			31
splice donor/acceptor (+/-2bp)	1	16	1	1	1	20
splice region			41	41	2	84
non coding			14	146	36	196
Total	114	48	1380	567	46

Highest pathogenic variant AF is 0.0000329

Variants in FANCM

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

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

Position	Type	Phenotype	Significance	ClinVar
14-45136027-G-A			Likely benign (Jul 22, 2024)
14-45136032-A-G		Fanconi anemia	Uncertain significance (Feb 11, 2021)
14-45136037-C-T		Fanconi anemia	Likely benign (Sep 18, 2022)
14-45136040-A-G		Fanconi anemia	Likely benign (May 29, 2020)
14-45136042-G-A		Fanconi anemia	Uncertain significance (Mar 20, 2023)
14-45136045-A-G		Fanconi anemia	Uncertain significance (Apr 08, 2022)
14-45136046-A-G		Fanconi anemia	Likely benign (Feb 01, 2024)
14-45136048-G-T		Fanconi anemia	Uncertain significance (Oct 04, 2022)
14-45136054-T-A		Fanconi anemia	Uncertain significance (Sep 18, 2023)
14-45136057-T-G			Uncertain significance (Jan 25, 2023)
14-45136061-G-A		Fanconi anemia • Hereditary cancer-predisposing syndrome • FANCM-related disorder	Conflicting classifications of pathogenicity (Sep 27, 2024)
14-45136062-A-T			Uncertain significance (Oct 26, 2023)
14-45136067-G-T		not specified • Fanconi anemia	Uncertain significance (Jun 07, 2021)
14-45136077-A-G		Fanconi anemia	Uncertain significance (May 09, 2023)
14-45136082-C-T		Fanconi anemia	Likely benign (Apr 02, 2021)
14-45136083-C-T		Fanconi anemia	Pathogenic (Mar 08, 2022)
14-45136084-G-A		Fanconi anemia • Spermatogenic failure 28;Premature ovarian failure 15 • Fanconi anemia complementation group A • not specified • Premature ovarian failure 15	Conflicting classifications of pathogenicity (Sep 11, 2024)
14-45136085-A-G		Fanconi anemia	Likely benign (Dec 24, 2020)
14-45136087-C-T		Fanconi anemia • Spermatogenic failure 28;Premature ovarian failure 15	Uncertain significance (Apr 26, 2022)
14-45136090-C-G		Fanconi anemia • Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Mar 28, 2024)
14-45136094-G-C		Fanconi anemia	Likely benign (Feb 19, 2022)
14-45136099-C-A		Fanconi anemia	Uncertain significance (Jul 24, 2023)
14-45136100-G-C		Fanconi anemia	Likely benign (Jan 24, 2024)
14-45136101-G-C		Fanconi anemia	Uncertain significance (Jan 28, 2022)
14-45136102-G-T		Fanconi anemia • Spermatogenic failure 28;Premature ovarian failure 15	Uncertain significance (Oct 27, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FANCM	protein_coding	protein_coding	ENST00000267430	23	64951

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.35e-15	1.00	125351	1	396	125748	0.00158

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.132	1053	1.04e+3	1.01	0.0000530	13597
Missense in Polyphen		154	191.55	0.80398		2398
Synonymous	-0.00495	369	369	1.00	0.0000191	3736
Loss of Function	4.73	40	87.9	0.455	0.00000463	1176

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00173	0.00173
Ashkenazi Jewish	0.00	0.00
East Asian	0.000218	0.000217
Finnish	0.00476	0.00477
European (Non-Finnish)	0.00151	0.00151
Middle Eastern	0.000218	0.000217
South Asian	0.00203	0.00199
Other	0.00212	0.00212

dbNSFP

Source: dbNSFP

• Function: FUNCTION: DNA-dependent ATPase component of the Fanconi anemia (FA) core complex (PubMed:16116422). Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage (PubMed:16116422, PubMed:19423727, PubMed:20347428, PubMed:20347429). In complex with CENPS and CENPX, binds double-stranded DNA (dsDNA), fork-structured DNA (fsDNA) and Holliday junction substrates (PubMed:20347428, PubMed:20347429). Its ATP-dependent DNA branch migration activity can process branched DNA structures such as a movable replication fork. This activity is strongly stimulated in the presence of CENPS and CENPX (PubMed:20347429). In complex with FAAP24, efficiently binds to single-strand DNA (ssDNA), splayed-arm DNA, and 3'-flap substrates (PubMed:17289582). In vitro, on its own, strongly binds ssDNA oligomers and weakly fsDNA, but does not bind to dsDNA (PubMed:16116434). {ECO:0000269|PubMed:16116422, ECO:0000269|PubMed:16116434, ECO:0000269|PubMed:17289582, ECO:0000269|PubMed:19423727, ECO:0000269|PubMed:20347428, ECO:0000269|PubMed:20347429}.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);Fanconi Anemia Pathway;DNA Repair;Fanconi anemia pathway (Consensus)

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.960
• rvis_EVS: 1.12
• rvis_percentile_EVS: 92.08

Haploinsufficiency Scores

• pHI: 0.0676
• hipred: Y
• hipred_score: 0.508
• ghis: 0.539

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.516

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fancm
• Phenotype: liver/biliary system phenotype; neoplasm; 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; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: resolution of meiotic recombination intermediates;replication fork processing;DNA duplex unwinding;interstrand cross-link repair;nucleic acid phosphodiester bond hydrolysis;positive regulation of protein monoubiquitination
• Cellular component: nucleoplasm;Fanconi anaemia nuclear complex;FANCM-MHF complex
• Molecular function: DNA binding;chromatin binding;nuclease activity;protein binding;ATP binding;ATP-dependent 3'-5' DNA helicase activity