SMC3
protein-codingstructural maintenance of chromosomes 3, the group of Proteoglycans|Cohesin complex|Structural maintenance of chromosomes proteins
Gene summary
This gene belongs to the SMC3 subfamily of SMC proteins. The encoded protein occurs in certain cell types as either an intracellular, nuclear protein or a secreted protein. The nuclear form, known as structural maintenance of chromosomes 3, is a component of the multimeric cohesin complex that holds together sister chromatids during mitosis, enabling proper chromosome segregation. Post-translational modification of the encoded protein by the addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [provided by RefSeq, Jul 2008]
- CSPG6
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: ClinGen
SMC3 was first reported in relation to autosomal dominant Cornelia de Lange syndrome as early as 2007 (Deardorff et al., PMID: 17273969). At least 17 unique variants including missense, in-frame indel, and nonsense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 17 probands, with 9 included in this curation to reach a definitive classification (PMID: 17273969, 25125236, 25655089, 25574841, 28781842). Variants in this gene segregated with disease in 1 additional family member. The mechanism of disease is proposed to be dominant negative. This gene-disease association is supported by an animal model, protein interactions, and in vitro functional assays (PMID: 18996922, 11983169, 23106691, 28408410). In summary, SMC3 is definitively associated with autosomal dominant Cornelia de Lange syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0012555
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012555
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012555
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMC3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005445.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 131 | 6 | 147 | ||
| missense | 12 | 56 | 239 | 20 | 327 | |
| nonsense | 8 | 4 | 8 | 20 | ||
| start loss | 0 | |||||
| frameshift | 4 | 4 | 6 | 14 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 8 | 12 | ||
| Total | 25 | 67 | 271 | 151 | 6 | 520 |
Highest pathogenic variant AF is 0.000006569439
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005436.1 | 29 | MANE Select | |
| Ensembl | ENSP00000354720.5 | 29 | MANE Select | |
| Ensembl | ENSP00000571846.1 | 25 | Standard | |
| Ensembl | ENSP00000588314.1 | 28 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smc3 | Danio rerio | Structure: cell Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Oocyte meiosis - Homo sapiens (human)
- Retinoblastoma (RB) in Cancer
- MECP2 and Associated Rett Syndrome
- Prion disease pathway
Biological Process
- mitotic cell cycle
- regulation of DNA replication
- DNA repair
- sister chromatid cohesion
- stem cell population maintenance
Molecular Function
- chromatin binding
- microtubule motor activity
- protein binding
- ATP binding
- mediator complex binding
Cellular Component
- chromosome, centromeric region
- chromatin
- lateral element
- basement membrane
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361804
- Coding exons
- 29
- Length
- 36946
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125739
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 6.40 | 178 | 630 | 0.283 | 0.0000325 | 8109 |
| Missense (PolyPhen) | 21 | 182.52 | 0.11506 | 2197 | ||
| Synonymous | -0.648 | 215 | 203 | 1.06 | 0.00000980 | 2091 |
| Loss of Function | 8.26 | 0 | 79.5 | 0.00 | 0.00000454 | 937 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex plays also an important role in spindle pole assembly during mitosis and in chromosomes movement. {ECO:0000269|PubMed:11076961, ECO:0000269|PubMed:19907496}.;
- Disease
- DISEASE: Cornelia de Lange syndrome 3 (CDLS3) [MIM:610759]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. Characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. Cornelia de Lange syndrome type 3 is a mild form with absence of major structural anomalies. The phenotype in some instances approaches that of apparently non- syndromic mental retardation. {ECO:0000269|PubMed:17273969, ECO:0000269|PubMed:18996922}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0988
Intolerance Scores
- LoFtool
- 0.0496
- RVIS EVS
- -0.89
- RVIS percentile EVS
- 10.3
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |