rs773773579
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.203_204insTT(p.Leu68PhefsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000562 in 1,602,538 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SPG11
NM_025137.4 frameshift
NM_025137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.50
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 15-44663444-C-CAA is Pathogenic according to our data. Variant chr15-44663444-C-CAA is described in ClinVar as [Pathogenic]. Clinvar id is 586640.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.203_204insTT | p.Leu68PhefsTer2 | frameshift_variant | 1/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.203_204insTT | p.Leu68PhefsTer2 | frameshift_variant | 1/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000231 AC: 5AN: 216866Hom.: 0 AF XY: 0.0000168 AC XY: 2AN XY: 119388
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GnomAD4 exome AF: 0.00000414 AC: 6AN: 1450294Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2AN XY: 720594
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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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, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 30, 2023 | This sequence change creates a premature translational stop signal (p.Leu68Phefs*2) 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 (rs773773579, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with multiple congenital anomalies (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 586640). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 25, 2018 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at