Coffin-Siris syndrome 5

Summary

Coffin-Siris syndrome 5 (MONDO:0014838) is a disease caused by SMARCE1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SMARCE1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Coffin-Siris syndrome 5
Mondo ID	MONDO:0014838
OMIM	616938
DOID	DOID:0112368
UMLS	C4310788
MedGen	934755
GARD	0016170
Is cancer (heuristic)	no

Also known as: Coffin-Siris syndrome 5 · Coffin-Siris syndrome caused by mutation in SMARCE1 · Coffin-Siris syndrome type 5 · CSS5 · SMARCE1 Coffin-Siris syndrome

Data availability: 29 ClinVar variants · 4 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 5

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 12, 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

29 retrieved; paginated sample, class counts are floors:

15 conflicting classifications of pathogenicity, 7 uncertain significance, 3 pathogenic, 3 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
212264	NM_003079.5(SMARCE1):c.624_627del (p.Ser208fs)	SMARCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
225845	NM_003079.5(SMARCE1):c.218A>C (p.Tyr73Ser)	SMARCE1	Pathogenic	no assertion criteria provided
666261	NM_003079.5(SMARCE1):c.237+1G>T	SMARCE1	Pathogenic	criteria provided, multiple submitters, no conflicts
30316	NM_003079.5(SMARCE1):c.218A>G (p.Tyr73Cys)	SMARCE1	Likely pathogenic	criteria provided, single submitter
4077082	NM_003079.5(SMARCE1):c.285G>C (p.Glu95Asp)	SMARCE1	Likely pathogenic	criteria provided, single submitter
559876	NM_003079.5(SMARCE1):c.276G>C (p.Lys92Asn)	SMARCE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403590	NM_003079.5(SMARCE1):c.1010A>G (p.Asn337Ser)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407066	NM_003079.5(SMARCE1):c.955G>A (p.Val319Ile)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407070	NM_003079.5(SMARCE1):c.767A>G (p.Lys256Arg)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
407075	NM_003079.5(SMARCE1):c.922G>A (p.Ala308Thr)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463421	NM_003079.5(SMARCE1):c.1210A>G (p.Ile404Val)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463422	NM_003079.5(SMARCE1):c.174G>A (p.Thr58=)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
463425	NM_003079.5(SMARCE1):c.488G>A (p.Arg163His)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486508	NM_003079.5(SMARCE1):c.1006G>A (p.Glu336Lys)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486509	NM_003079.5(SMARCE1):c.412G>A (p.Ala138Thr)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532246	NM_003079.5(SMARCE1):c.823G>A (p.Gly275Ser)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532249	NM_003079.5(SMARCE1):c.1067A>G (p.Asn356Ser)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
643758	NM_003079.5(SMARCE1):c.1231G>A (p.Glu411Lys)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704815	NM_003079.5(SMARCE1):c.63C>T (p.Ser21=)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
793950	NM_003079.5(SMARCE1):c.370-10T>C	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857521	NM_003079.5(SMARCE1):c.1009A>T (p.Asn337Tyr)	SMARCE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029667	NM_003079.5(SMARCE1):c.1036C>A (p.His346Asn)	SMARCE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1747265	NM_003079.5(SMARCE1):c.539A>G (p.Asp180Gly)	SMARCE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436142	NM_003079.5(SMARCE1):c.772A>G (p.Lys258Glu)	SMARCE1	Uncertain significance	criteria provided, single submitter
3581941	NM_003079.5(SMARCE1):c.514A>T (p.Ser172Cys)	SMARCE1	Uncertain significance	criteria provided, single submitter
3777103	NM_003079.5(SMARCE1):c.213G>T (p.Met71Ile)	SMARCE1	Uncertain significance	criteria provided, single submitter
4056094	NM_003079.5(SMARCE1):c.545A>G (p.Tyr182Cys)	SMARCE1	Uncertain significance	criteria provided, single submitter
532250	NM_003079.5(SMARCE1):c.487C>T (p.Arg163Cys)	SMARCE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
239497	NM_003079.5(SMARCE1):c.963G>A (p.Glu321=)	SMARCE1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
SMARCE1	Strong	Autosomal dominant	Coffin-Siris syndrome 5	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCE1	Orphanet:1465	Coffin-Siris syndrome
SMARCE1	Orphanet:2495	Meningioma
SMARCE1	Orphanet:263662	Familial multiple meningioma

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
SMARCE1	HGNC:11109	ENSG00000073584	Q969G3	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCE1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

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)
SMARCE1	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf

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
calcaneal tendon	1
embryo	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCE1	197	ubiquitous	marker	calcaneal tendon, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCE1	2,977

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCE1	Q969G3	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Formation of the canonical BAF (cBAF) complex	1	634.4×	0.010	SMARCE1
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.010	SMARCE1
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.010	SMARCE1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.010	SMARCE1
Regulation of endogenous retroelements	1	368.4×	0.010	SMARCE1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.010	SMARCE1
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.010	SMARCE1
MITF-M-dependent gene expression	1	181.3×	0.013	SMARCE1
RMTs methylate histone arginines	1	146.4×	0.013	SMARCE1
Transcriptional regulation by RUNX1	1	146.4×	0.013	SMARCE1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.014	SMARCE1
MITF-M-regulated melanocyte development	1	114.2×	0.014	SMARCE1
Chromatin organization	1	81.6×	0.018	SMARCE1
Chromatin modifying enzymes	1	72.3×	0.018	SMARCE1
Epigenetic regulation of gene expression	1	71.4×	0.018	SMARCE1
RNA Polymerase II Transcription	1	22.5×	0.053	SMARCE1
Gene expression (Transcription)	1	17.8×	0.063	SMARCE1
Generic Transcription Pathway	1	15.1×	0.069	SMARCE1
Developmental Biology	1	14.5×	0.069	SMARCE1

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
nucleosome disassembly	1	802.5×	0.005	SMARCE1
regulation of G0 to G1 transition	1	674.1×	0.005	SMARCE1
regulation of nucleotide-excision repair	1	601.9×	0.005	SMARCE1
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.005	SMARCE1
positive regulation of T cell differentiation	1	455.5×	0.005	SMARCE1
positive regulation of myoblast differentiation	1	366.4×	0.005	SMARCE1
positive regulation of stem cell population maintenance	1	343.9×	0.005	SMARCE1
positive regulation of double-strand break repair	1	343.9×	0.005	SMARCE1
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.005	SMARCE1
positive regulation of cell differentiation	1	267.5×	0.005	SMARCE1
neurogenesis	1	208.1×	0.006	SMARCE1
chromatin remodeling	1	73.0×	0.016	SMARCE1
negative regulation of DNA-templated transcription	1	31.6×	0.034	SMARCE1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SMARCE1

Therapeutics

Drug target analysis

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

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
SMARCE1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCE1	7	Binding:7

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	SMARCE1

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)
SMARCE1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.