Immunodeficiency-centromeric instability-facial anomalies syndrome 1

Summary

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (MONDO:0009454) is a disease caused by DNMT3B (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: DNMT3B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 142

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency-centromeric instability-facial anomalies syndrome 1
Mondo ID	MONDO:0009454
OMIM	242860
DOID	DOID:0090008
NCIT	C156430
UMLS	C4551557
MedGen	1636193
GARD	0015188
Is cancer (heuristic)	no

Also known as: DNMT3B immunodeficiency-centromeric instability-facial anomalies syndrome · ICF1 · immunodeficiency-centromeric instability-facial anomalies syndrome 1 · immunodeficiency-centromeric instability-facial anomalies syndrome caused by mutation in DNMT3B · immunodeficiency-centromeric instability-Facial anomalies syndrome type 1 · immunodeficiency-centromeric instability-facial anomalies syndrome type 1

Data availability: 142 ClinVar variants · 4 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › immunodeficiency-centromeric instability-facial anomalies syndrome › immunodeficiency-centromeric instability-facial anomalies syndrome 1

Related subtypes (3): immunodeficiency-centromeric instability-facial anomalies syndrome 2, immunodeficiency-centromeric instability-facial anomalies syndrome 3, immunodeficiency-centromeric instability-facial anomalies syndrome 4

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

142 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 37 conflicting classifications of pathogenicity, 15 benign, 9 pathogenic, 7 benign/likely benign, 6 pathogenic/likely pathogenic, 4 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
657788	NM_006892.4(DNMT3B):c.2348_2349del (p.Gln783fs)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6733	NM_006892.4(DNMT3B):c.2450A>G (p.Asp817Gly)	DNMT3B	Pathogenic	no assertion criteria provided
6734	NM_006892.4(DNMT3B):c.2452G>A (p.Val818Met)	DNMT3B	Pathogenic	criteria provided, multiple submitters, no conflicts
6735	NM_006892.4(DNMT3B):c.2177T>G (p.Val726Gly)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6736	NM_006892.4(DNMT3B):c.1987G>A (p.Gly663Ser)	DNMT3B	Pathogenic	no assertion criteria provided
6737	DNMT3B, LEU656THR	DNMT3B	Pathogenic	no assertion criteria provided
6738	DNMT3B, EX21-22DEL	DNMT3B	Pathogenic	no assertion criteria provided
6739	DNMT3B, 1-BP INS, CODON 53	DNMT3B	Pathogenic	no assertion criteria provided
6740	NM_006892.4(DNMT3B):c.1807G>A (p.Ala603Thr)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6741	NM_006892.4(DNMT3B):c.2421-11G>A	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6742	NM_006892.4(DNMT3B):c.2237T>G (p.Val746Gly)	DNMT3B	Pathogenic	no assertion criteria provided
6743	NM_006892.4(DNMT3B):c.88C>T (p.Gln30Ter)	DNMT3B	Pathogenic	no assertion criteria provided
6745	NM_006892.4(DNMT3B):c.808T>C (p.Ser270Pro)	DNMT3B	Pathogenic	no assertion criteria provided
803606	NM_006892.4(DNMT3B):c.2476C>T (p.Arg826Cys)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
952837	NM_006892.4(DNMT3B):c.1838T>C (p.Val613Ala)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683645	NM_006892.4(DNMT3B):c.2467C>G (p.Arg823Gly)	DNMT3B	Likely pathogenic	criteria provided, single submitter
1705256	NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)	DNMT3B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4847680	NM_006892.4(DNMT3B):c.2428G>T (p.Gly810Cys)	DNMT3B	Likely pathogenic	criteria provided, single submitter
6744	NM_006892.4(DNMT3B):c.2519G>A (p.Arg840Gln)	DNMT3B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1026466	NM_006892.4(DNMT3B):c.2477G>A (p.Arg826His)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1324289	NM_006892.4(DNMT3B):c.2506G>A (p.Val836Met)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3336375	NM_006892.4(DNMT3B):c.2162T>C (p.Ile721Thr)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338151	NM_006892.4(DNMT3B):c.115G>C (p.Glu39Gln)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338152	NM_006892.4(DNMT3B):c.143-9C>G	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338153	NM_006892.4(DNMT3B):c.143-8C>T	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338154	NM_006892.4(DNMT3B):c.158C>T (p.Ser53Leu)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338156	NM_006892.4(DNMT3B):c.516C>T (p.Asp172=)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338157	NM_006892.4(DNMT3B):c.895C>A (p.Arg299=)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338159	NM_006892.4(DNMT3B):c.922-8C>T	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338161	NM_006892.4(DNMT3B):c.1035C>T (p.Ile345=)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
DNMT3B	Definitive	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNMT3B	Orphanet:2268	ICF syndrome
DNMT3B	Orphanet:269	Facioscapulohumeral dystrophy

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
DNMT3B	HGNC:2979	ENSG00000088305	Q9UBC3	DNA (cytosine-5)-methyltransferase 3B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNMT3B	DNA (cytosine-5)-methyltransferase 3B	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT3B	Transcription factor	no	2.1.1.37	PWWP_dom, C5_MeTfrase, Znf_FYVE_PHD

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
hair follicle	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT3B	184	ubiquitous	marker	secondary oocyte, oocyte, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3B	4,378

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3B	Q9UBC3	47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
SUMOylation of DNA methylation proteins	1	671.8×	0.007	DNMT3B
DNA methylation	1	178.4×	0.008	DNMT3B
Defective pyroptosis	1	156.4×	0.008	DNMT3B
PRC2 methylates histones and DNA	1	152.3×	0.008	DNMT3B
NoRC negatively regulates rRNA expression	1	104.8×	0.010	DNMT3B

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
methylation	1	170.2×	0.018	DNMT3B
positive regulation of gene expression	1	38.7×	0.039	DNMT3B
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	DNMT3B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNMT3B	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NANAFROCIN	2	DNMT3B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DNMT3B	76	Binding:75, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3B	2.1.1.37	DNA (cytosine-5-)-methyltransferase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
NANAFROCIN	2	DNMT3B

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	1	DNMT3B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.