STAG1

protein-coding

stromal antigen 1, the group of Armadillo like helical domain containing|Cohesin complex

Gene summary

This gene is a member of the SCC3 family and is expressed in the nucleus. It encodes a component of cohesin, a multisubunit protein complex that provides sister chromatid cohesion along the length of a chromosome from DNA replication through prophase and prometaphase, after which it is dissociated in preparation for segregation during anaphase. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005862.3

Inheritance

ClinVar variants

P:59U:315B:175

Top phenotype

Intellectual developmental disorder, autosomal dominant 47

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr3:136,336,236-136,752,403

External References & Databases

Ensembl (ENSG00000118007)

Transcript & Mutation Effects

hg38 • Region Span ~416.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal dominant 47STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030912

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 47STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030912

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 47DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030912

Submitter: G2P

intellectual developmental disorder, autosomal dominant 47MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030912

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*STAG1* was first reported in relation to autosomal dominant intellectual disability with syndromic features in 2017 (Lehalle et al., PMID: 28119487). Phenotypes reported with *STAG1* variants most frequently include intellectual disability, autism, seizures, hypotonia, hyperlaxity, and dysmorphic features. Considering the additional features that present with intellectual disability, variants in this gene have been curated for disease assertion “complex neurodevelopmental disorder”. Fourteen variants (missense and frameshift) in 14 probands, reported in three publications (PMIDs: 30158690, 34440290, 28119487) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is believed to be haploinsufficiency (PMID: 28119487). No experimental evidence currently supports this gene-disease relationship. While one knockout mouse model has been reported, it was not scored as evidence due to insufficient face validity regarding the human phenotype (PMID: 22415365). In summary, there is definitive evidence to support the relationship between *STAG1* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on September 20, 2022 (SOP 9).

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 47AD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency

Refs: 28119487

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STAG1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 534

Inborn genetic diseasesTotal: 96

Intellectual disability, autosomal dominant 47Total: 74

not specifiedTotal: 70

STAG1-related disorderTotal: 39

Neurodevelopmental disorderTotal: 2

See casesTotal: 2

Congenital ocular colobomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005862.3. 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			5 clinvar	120 clinvar	7 clinvar	132
missense	1 clinvar	16 clinvar	299 clinvar	43 clinvar	5 clinvar	364
nonsense	8 clinvar	8 clinvar	1 clinvar			17
start loss						0
frameshift	6 clinvar	14 clinvar	1 clinvar			21
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	9 clinvar			15
Total	16	43	315	163	12	549

Highest pathogenic variant AF is 0.000006570734

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005862.3	RefSeq	NP_005853.2	33	MANE Select
ENST00000383202.7	Ensembl	ENSP00000372689.2	33	MANE Select
ENST00000236698.10	Ensembl	ENSP00000236698.5	32	Standard
ENST00000236698.9	Ensembl	ENSP00000236698.5	32	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell cycle - Homo sapiens (human)
Regulation of sister chromatid separation at the metaphase-anaphase transition
Signal Transduction
SUMOylation of DNA damage response and repair proteins
Post-translational protein modification

Biological Process

cell cycle
chromosome segregation
sister chromatid cohesion
positive regulation of transcription by RNA polymerase II
cell division

Molecular Function

DNA-binding transcription activator activity, RNA polymerase II-specific
chromatin binding
protein binding

Cellular Component

chromosome, centromeric region
chromatin
nucleus
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000383202
Coding exons: 33
Length: 416144
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125731
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.44	338	659	0.513	0.0000334	8363
Missense (PolyPhen)		37	177.12	0.2089		2368
Synonymous	-0.894	239	222	1.08	0.0000110	2247
Loss of Function	7.69	4	76.7	0.0521	0.00000429	919

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00022	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms 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. The cohesin complex may also play a role in spindle pole assembly during mitosis.;
Disease: DISEASE: Mental retardation, autosomal dominant 47 (MRD47) [MIM:617635]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD47 patients manifest developmental delay and mild to moderate intellectual disability, usually with delayed speech. {ECO:0000269|PubMed:28119487}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.141

Intolerance Scores

LoFtool: 0.214
RVIS EVS: -1.04
RVIS percentile EVS: 7.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.934

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium