SPAG8

protein-coding

sperm associated antigen 8

Gene summary

The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein encoded by this gene is recognized by sperm agglutinating antibodies from an infertile woman. This protein is localized in germ cells of the testis at all stages of spermatogenesis and is localized to the acrosomal region of mature spermatozoa. This protein interacts with ACT (activator of CREM in testis) and may play a role in CREM (cAMP response element modulator)-ACT-mediated gene transcription during spermatogenesis. This protein may also play a role in spermatogenesis by regulating microtubule formation and cell division. Alternatively spliced variants that encode different protein isoforms have been described but the full-length sequences of only two have been determined. [provided by RefSeq, Jul 2012]

MANE transcript

NM_001039592.2

Inheritance

—

ClinVar variants

U:82B:11

Top phenotype

Primary ciliary dyskinesia

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr9:35,808,045-35,812,272

External References & Databases

Ensembl (ENSG00000137098)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC 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 SPAG8 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 81

not providedTotal: 9

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039592.2. 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			2 clinvar	2 clinvar	3 clinvar	7
missense			78 clinvar	2 clinvar	3 clinvar	83
nonsense					1 clinvar	1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	82	4	7	93

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039592.2	RefSeq	NP_001034681.1	7	MANE Select
ENST00000396638.7	Ensembl	ENSP00000379878.2	7	MANE Select
NM_001366760.2	RefSeq	NP_001353689.1	6	Standard
NM_172312.2	RefSeq	NP_758516.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell cycle
spermatogenesis
single fertilization
biological_process
cell differentiation

Molecular Function

molecular_function
protein binding
microtubule binding

Cellular Component

acrosomal vesicle
nucleus
cytoplasm
spindle
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340291
Coding exons: 8
Length: 4228
Individuals with no LoFs: 122844
Homozygous LoFs: 77
Heterozygous LoFs: 2827
Defined: 125748
p: 0.0116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.568	253	280	0.905	0.0000145	3211
Missense (PolyPhen)		39	56.01	0.69631		686
Synonymous	0.128	106	108	0.984	0.00000583	1054
Loss of Function	0.617	20	23.2	0.862	0.00000126	235

Population LoF Frequency

Population	CAF	p-value	Status
African	0.014	0.015	notable
Latino/Admixed American	0.0053	0.0052	notable
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.079	0.079	notable
Finnish	0.043	0.036	notable
European (Non-Finnish)	0.0020	0.0020	notable
South Asian	0.0018	0.0018	notable
Other	0.0061	0.0059	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in spermatogenesis by enhancing the binding of CREM isoform tau to its coactivator FHL5 and increasing the FHL5-regulated transcriptional activation of CREM isoform tau (By similarity). Involved in the acrosome reaction and in binding of sperm to the zona pellucida (By similarity). Plays a role in regulation of the cell cycle by controlling progression through the G2/M phase, possibly by delaying the activation of CDK1 which is required for entry into mitosis (PubMed:19548270). May play a role in fertility and microtubule formation through interaction with RANBP9 (PubMed:10500252). {ECO:0000250|UniProtKB:Q3V0Q6, ECO:0000269|PubMed:10500252, ECO:0000269|PubMed:19548270}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.927
RVIS EVS: 0.87
RVIS percentile EVS: 88.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.265

Gene Damage Prediction

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