STAG3

protein-coding

stromal antigen 3, the group of Armadillo like helical domain containing|Cohesin complex

Gene summary

The protein encoded by this gene is expressed in the nucleus and is a subunit of the cohesin complex which regulates the cohesion of sister chromatids during cell division. A mutation in this gene is associated with premature ovarian failure. Alternate splicing results in multiple transcript variants encoding distinct isoforms. This gene has multiple pseudogenes. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001282717.2

Inheritance

ClinVar variants

P:28U:163B:29

Top phenotype

Premature ovarian failure 8

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr7:100,177,563-100,214,387

External References & Databases

Ensembl (ENSG00000066923)

Transcript & Mutation Effects

hg38 • Region Span ~36.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 61LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030507

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014321

Submitter: Labcorp Genetics (formerly Invitae)

spermatogenic failure 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030507

Submitter: PanelApp Australia

premature ovarian failure 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014321

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Premature ovarian failure 8AR

Manifestation: Endocrine; Genitourinary; Obstetric

Intervention: Obstetric

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

Comments: One described individual was reported as additionally affected by ovarian cancer

Refs: 22428046; 24597867; 26059840; 31125047; 31682730; 32634216

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STAG3 variants in ClinVar

16 Conditions Cataloged

Inborn genetic diseasesTotal: 150

not providedTotal: 33

Premature ovarian failure 8Total: 17

STAG3-related disorderTotal: 13

Spermatogenic failure 61Total: 8

not specifiedTotal: 8

Non-obstructive azoospermiaTotal: 4

Premature ovarian insufficiencyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001282717.2. 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			3 clinvar	15 clinvar		18
missense		2 clinvar	153 clinvar	14 clinvar		169
nonsense	4 clinvar	5 clinvar				9
start loss						0
frameshift	6 clinvar	7 clinvar				13
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	7 clinvar			11
Total	11	17	163	29	0	220

Highest pathogenic variant AF is 0.000124558

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001282717.2	RefSeq	NP_001269646.1	33	MANE Select
ENST00000615138.5	Ensembl	ENSP00000477973.1	33	MANE Select
NM_001282716.1	RefSeq	NP_001269645.1	33	Standard
NM_001282718.2	RefSeq	NP_001269647.1	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oocyte meiosis - Homo sapiens (human)
Reproduction
Meiotic synapsis
Meiosis
Cell Cycle

Biological Process

sister chromatid cohesion
synaptonemal complex assembly

Molecular Function

chromatin binding

Cellular Component

chromosome, centromeric region
chromatin
synaptonemal complex
extracellular space
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000426455
Coding exons: 33
Length: 43926
Individuals with no LoFs: 125614
Homozygous LoFs: 0
Heterozygous LoFs: 134
Defined: 125748
p: 0.000533

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.66	569	692	0.823	0.0000403	8033
Missense (PolyPhen)		123	177.26	0.69388		2040
Synonymous	1.08	253	276	0.917	0.0000159	2388
Loss of Function	4.32	33	72.8	0.453	0.00000379	819

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00064	0.00064	rare
South Asian	0.00076	0.00075	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Meiosis specific component of cohesin complex. The cohesin complex is 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 meiosis- specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I. {ECO:0000250|UniProtKB:O70576}.;
Disease: DISEASE: Premature ovarian failure 8 (POF8) [MIM:615723]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:24597867, ECO:0000303|PubMed:22428046}. Note=The disease is caused by mutations affecting the gene represented in this entry. A homozygous deletion in STAG3 predicted to result in frameshift and premature truncation, has been shown to be the cause of premature ovarian failure in a large consanguineous family. {ECO:0000269|PubMed:24597867}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.921
RVIS EVS: -1.1
RVIS percentile EVS: 6.91

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.680

Gene Damage Prediction

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