chr8-100177834-A-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003114.5(SPAG1):c.319A>T(p.Lys107Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,533,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: 0.0000014 ( 0 hom. )
Consequence
SPAG1
NM_003114.5 stop_gained
NM_003114.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.07
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 8-100177834-A-T is Pathogenic according to our data. Variant chr8-100177834-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 410980.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPAG1 | NM_003114.5 | c.319A>T | p.Lys107Ter | stop_gained | 4/19 | ENST00000388798.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAG1 | ENST00000388798.7 | c.319A>T | p.Lys107Ter | stop_gained | 4/19 | 1 | NM_003114.5 | P1 | |
SPAG1 | ENST00000251809.4 | c.319A>T | p.Lys107Ter | stop_gained | 4/19 | 5 | P1 | ||
SPAG1 | ENST00000520508.5 | c.319A>T | p.Lys107Ter | stop_gained | 4/10 | 5 | |||
SPAG1 | ENST00000520643.5 | c.319A>T | p.Lys107Ter | stop_gained | 4/10 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000822 AC: 2AN: 243220Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131866
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GnomAD4 exome AF: 0.00000145 AC: 2AN: 1381154Hom.: 0 Cov.: 24 AF XY: 0.00000289 AC XY: 2AN XY: 691434
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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 | Invitae | Feb 09, 2021 | This variant is present in population databases (rs752479330, ExAC 0.004%). 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. ClinVar contains an entry for this variant (Variation ID: 410980). This sequence change creates a premature translational stop signal (p.Lys107*) in the SPAG1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at