Premature ovarian failure 15

Summary

Premature ovarian failure 15 (MONDO:0054862) is a disease caused by FANCM (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FANCM (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 320

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	premature ovarian failure 15
Mondo ID	MONDO:0054862
OMIM	618096
DOID	DOID:0080872
UMLS	C4748170
MedGen	1648369
GARD	0025989
Is cancer (heuristic)	no

Also known as: POF15 · premature ovarian failure 15

Data availability: 320 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › premature ovarian failure 15

Related subtypes (6): bone marrow failure syndrome, osteomyelitis, bone marrow neoplasm, polycythemia, Fanconi anemia, Drachtman Weinblatt Sitarz syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

320 retrieved; paginated sample, class counts are floors:

216 uncertain significance, 33 conflicting classifications of pathogenicity, 26 likely benign, 20 benign/likely benign, 10 benign, 9 pathogenic/likely pathogenic, 5 likely pathogenic, 1 likely pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072585	NM_020937.4(FANCM):c.1492C>T (p.Gln498Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2052771	NM_020937.4(FANCM):c.3088C>T (p.Arg1030Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208640	NM_020937.4(FANCM):c.1491dup (p.Gln498fs)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2770796	NM_020937.4(FANCM):c.865_881del (p.Lys288_Leu289insTer)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
412519	NM_020937.4(FANCM):c.5101C>T (p.Gln1701Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444327	NM_020937.4(FANCM):c.1972C>T (p.Arg658Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
526381	NM_020937.4(FANCM):c.5791C>T (p.Arg1931Ter)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545911	NM_020937.4(FANCM):c.2586_2589del (p.Lys863fs)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
936956	NM_020937.4(FANCM):c.4477del (p.Arg1493fs)	FANCM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627748	NM_020937.4(FANCM):c.1139_1140del (p.Arg380fs)	FANCM	Likely pathogenic, low penetrance	no assertion criteria provided
3576573	NM_020937.4(FANCM):c.760-2A>G	FANCM	Likely pathogenic	criteria provided, single submitter
3576584	NM_020937.4(FANCM):c.2956del (p.Val986fs)	FANCM	Likely pathogenic	criteria provided, single submitter
3576587	NM_020937.4(FANCM):c.3677del (p.Asp1226fs)	FANCM	Likely pathogenic	criteria provided, single submitter
3576589	NM_020937.4(FANCM):c.4637_4638insCATTACTTGACTCAACATTACTTGACTCAACTCAACTC (p.Leu1546delinsPheIleThrTer)	FANCM	Likely pathogenic	criteria provided, single submitter
4845781	NM_020937.4(FANCM):c.5972_5973del (p.Cys1991fs)	FANCM	Likely pathogenic	criteria provided, single submitter
1203713	NM_020937.4(FANCM):c.5152G>A (p.Val1718Met)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319687	NM_020937.4(FANCM):c.1397-14A>T	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1361430	NM_020937.4(FANCM):c.5066C>T (p.Ala1689Val)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1432374	NM_020937.4(FANCM):c.6010T>A (p.Ser2004Thr)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241318	NM_020937.4(FANCM):c.2517T>G (p.Ile839Met)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
261381	NM_020937.4(FANCM):c.1397-15TA[6]	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313188	NM_020937.4(FANCM):c.171G>C (p.Leu57Phe)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313199	NM_020937.4(FANCM):c.1576C>G (p.Leu526Val)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313200	NM_020937.4(FANCM):c.1741C>T (p.Arg581Cys)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313209	NM_020937.4(FANCM):c.2859A>C (p.Lys953Asn)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313218	NM_020937.4(FANCM):c.4366C>T (p.Arg1456Cys)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313220	NM_020937.4(FANCM):c.4627C>T (p.Leu1543Phe)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3576580	NM_020937.4(FANCM):c.1759A>G (p.Ile587Val)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
414849	NM_020937.4(FANCM):c.3296G>A (p.Arg1099His)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456253	NM_020937.4(FANCM):c.2267G>A (p.Arg756His)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FANCM	Strong	Autosomal recessive	spermatogenic failure 28	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FANCM	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FANCM	Orphanet:84	Fanconi anemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FANCM	HGNC:23168	ENSG00000187790	Q8IYD8	Fanconi anemia group M protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FANCM	Fanconi anemia group M protein	DNA-dependent ATPase component of the Fanconi anemia (FA) core complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FANCM	Other/Unknown	no		Helicase_C-like, ERCC4_domain, RuvA_2-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FANCM	203	ubiquitous	marker	sperm, oocyte, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCM	2,764

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FANCM	Q8IYD8	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fanconi Anemia Pathway	1	278.5×	0.007	FANCM
PKR-mediated signaling	1	141.0×	0.007	FANCM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
double-strand break repair via synthesis-dependent strand annealing	1	4213.0×	7e-04	FANCM
positive regulation of protein monoubiquitination	1	3370.4×	7e-04	FANCM
resolution of meiotic recombination intermediates	1	936.2×	0.002	FANCM
interstrand cross-link repair	1	432.1×	0.002	FANCM
replication fork processing	1	421.3×	0.002	FANCM

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FANCM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FANCM

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FANCM	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.