Coffin-Siris syndrome 12

Summary

Coffin-Siris syndrome 12 (MONDO:0025699) is a disease caused by BICRA (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: BICRA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 70

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 12
Mondo ID	MONDO:0025699
OMIM	619325
DOID	DOID:0112370
UMLS	C5444111
MedGen	1782096
GARD	0016443
Is cancer (heuristic)	no

Also known as: CSS12

Data availability: 70 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Coffin-Siris syndrome › Coffin-Siris syndrome 12

Related subtypes (10): Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, Coffin-Siris syndrome 5, Coffin-Siris syndrome 8, Coffin-Siris syndrome 10, Coffin-Siris syndrome 11, Coffin-Siris syndrome 7

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

70 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 16 pathogenic, 15 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1106676	NM_001394372.1(BICRA):c.1993C>T (p.Gln665Ter)	BICRA	Pathogenic	no assertion criteria provided
1106678	NM_001394372.1(BICRA):c.2479_2480delinsA (p.Ala827fs)	BICRA	Pathogenic	criteria provided, single submitter
1106681	NM_001394372.1(BICRA):c.192G>C (p.Glu64Asp)	BICRA	Pathogenic	no assertion criteria provided
1685570	NM_001394372.1(BICRA):c.3248+1G>A	BICRA	Pathogenic	criteria provided, single submitter
1708048	NM_001394372.1(BICRA):c.974_987dup (p.Gly330fs)	BICRA	Pathogenic	criteria provided, single submitter
1801348	NM_001394372.1(BICRA):c.1921C>T (p.Gln641Ter)	BICRA	Pathogenic	criteria provided, single submitter
2504582	NM_001394372.1(BICRA):c.639_669del (p.Leu214fs)	BICRA	Pathogenic	criteria provided, single submitter
2691554	NM_001394372.1(BICRA):c.3300C>A (p.Tyr1100Ter)	BICRA	Pathogenic	criteria provided, single submitter
2692500	NM_001394372.1(BICRA):c.1214_1215insT (p.Gln407fs)	BICRA	Pathogenic	criteria provided, single submitter
3376134	NM_001394372.1(BICRA):c.1163del (p.Pro388fs)	BICRA	Pathogenic	criteria provided, single submitter
3775980	NM_001394372.1(BICRA):c.1767_1770del (p.Pro590fs)	BICRA	Pathogenic	criteria provided, single submitter
4531728	NM_001394372.1(BICRA):c.706del (p.Gln236fs)	BICRA	Pathogenic	criteria provided, single submitter
4531729	NM_001394372.1(BICRA):c.848_849del (p.Gln283fs)	BICRA	Pathogenic	criteria provided, single submitter
4536614	NM_001394372.1(BICRA):c.229del (p.Leu77fs)	BICRA	Pathogenic	criteria provided, single submitter
4688214	NM_001394372.1(BICRA):c.1074del (p.Leu359fs)	BICRA	Pathogenic	criteria provided, single submitter
996135	NM_001394372.1(BICRA):c.3247dup (p.Cys1083fs)	BICRA	Pathogenic	no assertion criteria provided
1308646	NM_001394372.1(BICRA):c.386_401del (p.Phe129fs)	BICRA	Likely pathogenic	no assertion criteria provided
1700051	NM_001394372.1(BICRA):c.3529C>T (p.Arg1177Ter)	BICRA	Likely pathogenic	criteria provided, single submitter
1700052	NM_001394372.1(BICRA):c.4343dup (p.Pro1449fs)	BICRA	Likely pathogenic	criteria provided, single submitter
1801369	NM_001394372.1(BICRA):c.1509_1510insA (p.His504fs)	BICRA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441686	NM_001394372.1(BICRA):c.1933C>T (p.Gln645Ter)	BICRA	Likely pathogenic	criteria provided, single submitter
2504583	NM_001394372.1(BICRA):c.2734_2737del (p.Pro912fs)	BICRA	Likely pathogenic	criteria provided, single submitter
2504585	GRCh37/hg19 19q13.33(chr19:48197371-48246391)	BICRA	Likely pathogenic	criteria provided, single submitter
3238657	NM_001394372.1(BICRA):c.3246del (p.Cys1083fs)	BICRA	Likely pathogenic	no assertion criteria provided
3376496	NM_001394372.1(BICRA):c.2018G>C (p.Ser673Thr)	BICRA	Likely pathogenic	criteria provided, single submitter
3381238	NM_001394372.1(BICRA):c.2753_2754insC (p.Lys918fs)	BICRA	Likely pathogenic	criteria provided, single submitter
3765885	NM_001394372.1(BICRA):c.1887dup (p.Ala630fs)	BICRA	Likely pathogenic	criteria provided, single submitter
4293045	NM_001394372.1(BICRA):c.2104C>T (p.Gln702Ter)	BICRA	Likely pathogenic	criteria provided, single submitter
4813291	Single allele	BICRA	Likely pathogenic	criteria provided, single submitter
4819893	NM_001394372.1(BICRA):c.492del (p.Asp165fs)	BICRA	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
BICRA	Strong	Autosomal dominant	Coffin-Siris syndrome 12	3

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BICRA	HGNC:4332	ENSG00000063169	Q9NZM4	BRD4-interacting chromatin-remodeling complex-associated protein	gencc,clinvar
INAFM1	HGNC:27406	ENSG00000257704	C9JVW0	Putative transmembrane protein INAFM1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BICRA	BRD4-interacting chromatin-remodeling complex-associated protein	Component of SWI/SNF chromatin remodeling subcomplex GBAF that carries out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BICRA	Other/Unknown	no		GSCR1_dom, Chromatin_remod/trans_coact
INAFM1	Other/Unknown	no		InaF-motif

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
oocyte	1
secondary oocyte	1
decidua	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BICRA	267	ubiquitous	yes	oocyte, secondary oocyte, diaphragm
INAFM1	251	ubiquitous	marker	decidua, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BICRA	1,178
INAFM1	145

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
INAFM1	C9JVW0	60.01
BICRA	Q9NZM4	42.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.001	BICRA

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
positive regulation of stem cell population maintenance	1	343.9×	0.011	BICRA
negative regulation of cell differentiation	1	285.6×	0.011	BICRA
chromatin remodeling	1	73.0×	0.027	BICRA
positive regulation of cell population proliferation	1	33.6×	0.043	BICRA
positive regulation of DNA-templated transcription	1	27.9×	0.043	BICRA
regulation of transcription by RNA polymerase II	1	11.7×	0.086	BICRA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BICRA	1	2
INAFM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	BICRA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BICRA	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
MOLIBRESIB	2	BICRA

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	BICRA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	INAFM1

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)
INAFM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.