rs1380083184
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000388798.7(SPAG1):c.1864dup(p.Thr622AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000751 in 1,597,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
SPAG1
ENST00000388798.7 frameshift
ENST00000388798.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.76
Genes affected
SPAG1 (HGNC:11212): (sperm associated antigen 1) 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 expressed by this gene is recognized by anti-sperm agglutinating antibodies from an infertile woman. Furthermore, immunization of female rats with the recombinant human protein reduced fertility. This protein localizes to the plasma membrane of germ cells in the testis and to the post-acrosomal plasma membrane of mature spermatozoa. Recombinant polypeptide binds GTP and exhibits GTPase activity. Thus, this protein may regulate GTP signal transduction pathways involved in spermatogenesis and fertilization. Two transcript variants of this gene encode the same protein. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-100231158-G-GA is Pathogenic according to our data. Variant chr8-100231158-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 541532.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPAG1 | NM_003114.5 | c.1864dup | p.Thr622AsnfsTer3 | frameshift_variant | 15/19 | ENST00000388798.7 | NP_003105.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPAG1 | ENST00000388798.7 | c.1864dup | p.Thr622AsnfsTer3 | frameshift_variant | 15/19 | 1 | NM_003114.5 | ENSP00000373450 | P1 | |
SPAG1 | ENST00000251809.4 | c.1864dup | p.Thr622AsnfsTer3 | frameshift_variant | 15/19 | 5 | ENSP00000251809 | P1 | ||
SPAG1 | ENST00000523302.1 | n.518dup | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151838Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000692 AC: 10AN: 1446130Hom.: 0 Cov.: 29 AF XY: 0.00000556 AC XY: 4AN XY: 719622
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151838Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74132
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 28 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 10, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SPAG1 are known to be pathogenic (PMID: 24055112). This variant has not been reported in the literature in individuals with SPAG1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr622Asnfs*3) in the SPAG1 gene. It is expected to result in an absent or disrupted protein product. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at