rs587777921
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.4462_4463del(p.Val1488LeufsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,614,122 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 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SPG11
NM_025137.4 frameshift
NM_025137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 15-44595430-AAC-A is Pathogenic according to our data. Variant chr15-44595430-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 41317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.4462_4463del | p.Val1488LeufsTer13 | frameshift_variant | 26/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.4462_4463del | p.Val1488LeufsTer13 | frameshift_variant | 26/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251336Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135834
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727238
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74386
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:2
Pathogenic, no assertion criteria provided | curation | GeneReviews | Jan 31, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Val1488Leufs*13) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs780367421, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18408091). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
Computational scores
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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