rs779321661
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.5781_5782insGGAGGATCTG(p.His1928GlyfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,052 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: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
SPG11
NM_025137.4 frameshift
NM_025137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.142
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 15-44583898-G-GCAGATCCTCC is Pathogenic according to our data. Variant chr15-44583898-G-GCAGATCCTCC is described in ClinVar as [Pathogenic]. Clinvar id is 423138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SPG11 | NM_025137.4 | c.5781_5782insGGAGGATCTG | p.His1928GlyfsTer15 | frameshift_variant | 30/40 | ENST00000261866.12 | NP_079413.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SPG11 | ENST00000261866.12 | c.5781_5782insGGAGGATCTG | p.His1928GlyfsTer15 | frameshift_variant | 30/40 | 1 | NM_025137.4 | ENSP00000261866 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251412Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727238
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GnomAD4 genome 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
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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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.His1928Glyfs*15) 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 (rs779321661, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 423138). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2017 | The c.5772_5781dup10 pathogenic variant in the SPG11 gene causes a frameshift starting with codon Histidine 1928, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.H1928GfsX15. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret c.5772_5781dup10 as a pathogenic variant. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at