SPAG4
protein-codingsperm associated antigen 4, the group of SUN family
Gene summary
The mammalian sperm flagellum contains two cytoskeletal structures associated with the axoneme: the outer dense fibers surrounding the axoneme in the midpiece and principal piece and the fibrous sheath surrounding the outer dense fibers in the principal piece of the tail. Defects in these structures are associated with abnormal tail morphology, reduced sperm motility, and infertility. In the rat, the protein encoded by this gene associates with an outer dense fiber protein via a leucine zipper motif and localizes to the microtubules of the manchette and axoneme during sperm tail development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPAG4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003116.3. 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 | 1 | 1 | ||||
| missense | 57 | 1 | 58 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 62 | 1 | 0 | 63 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003107.1 | 12 | MANE Select | |
| Ensembl | ENSP00000363391.3 | 12 | MANE Select | |
| RefSeq | NP_001304860.1 | 12 | Standard | |
| Ensembl | ENSP00000399231.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- nuclear envelope organization
- spermatogenesis
- cell differentiation
- cytoskeletal anchoring at nuclear membrane
Molecular Function
- structural molecule activity
- protein binding
- protein membrane anchor
Cellular Component
- nuclear envelope
- nuclear inner membrane
- cytoplasm
- cytoskeleton
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374273
- Coding exons
- 12
- Length
- 5158
- Individuals with no LoFs
- 125479
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 269
- Defined
- 125748
- p
- 0.00107
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.983 | 201 | 244 | 0.823 | 0.0000119 | 2784 |
| Missense (PolyPhen) | 74 | 91.369 | 0.8099 | 1038 | ||
| Synonymous | 0.354 | 100 | 105 | 0.956 | 0.00000503 | 884 |
| Loss of Function | 1.75 | 14 | 23.1 | 0.607 | 9.88e-7 | 260 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00024 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.012 | 0.012 | notable |
| Finnish | 0.000099 | 0.000092 | rare |
| European (Non-Finnish) | 0.00020 | 0.00018 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00018 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in spermatogenesis. Required for sperm head formation but not required to establish and maintain general polarity of the sperm head. Required for anchoring and organization of the manchette. Required for targeting of SUN3 and probably SYNE1 through a probable SUN1:SYNE3 LINC complex to the nuclear envelope and involved in accurate posterior sperm head localization of the complex. May anchor SUN3 the nuclear envelope. Involved in maintenance of the nuclear envelope integrity. May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail. {ECO:0000250|UniProtKB:O55034, ECO:0000250|UniProtKB:Q9JJF2}.;
Recessive Scores
- pRec
- 0.111
Intolerance Scores
- LoFtool
- 0.781
- RVIS EVS
- 0.55
- RVIS percentile EVS
- 81.48
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.808
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |