rs312262776
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.5989_5992del(p.Leu1997MetfsTer60) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1997L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_025137.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.5989_5992del | p.Leu1997MetfsTer60 | frameshift_variant | 31/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.5989_5992del | p.Leu1997MetfsTer60 | frameshift_variant | 31/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251154Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135736
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461700Hom.: 0 AF XY: 0.0000234 AC XY: 17AN XY: 727176
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152300Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74472
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change creates a premature translational stop signal (p.Leu1997Metfs*60) 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 (rs312262776, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18079167, 18337587, 22237444). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.5985delCTGT and p.L1997MfsX2056. ClinVar contains an entry for this variant (Variation ID: 41335). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | Neurogenomics Lab, Neuroscience Institute, University Of Cape Town | May 22, 2024 | PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00008001 (0.008%; 5/62492 alleles in Remaining population) and in gnomAD v3.1.2 is 0.00002413 (0.002%; 1/ 41440 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PS4 not evaluated as literature probands counted under PM3. PP1_moderate: variant segregates with 2 informative meioses in 1 family. PM3_strong: 3 points awarded for 2 homozygous occurrences, 2 observations with pathogenic variant but phase unknown and 1 observation with pathogenic variant confirmed in trans (PMID 21625935, 18079167, 24571105, 18337587, 22237444). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 06, 2022 | PM2, PM3, PVS1 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2022 | Identified in individuals with features of spastic paraplegia type 11, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Stevanin et al., 2008; Stromillo et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21625935, 31589614, 18079167) - |
SPG11-related spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 27, 2020 | The SPG11 c.5989_5992delCTGT (p.Leu1997MetfsTer60) variant results in a frameshift and is predicted to result in a premature truncation of the protein. This variant has been reported in six individuals from four unrelated families diagnosed with spastic paraplegia, including in a homozygous state in four individuals from two consanguineous families and in a compound heterozygous state with a second predicted null variant in two individuals (Stevanin et al. 2008; Paisan-Ruiz et al. 2008; Stromillo et al. 2011; Conceicao Pereira et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000026 in the European (non-Finnish) population of the Genome Aggregation Consortium. Based on the predicted truncating nature of the variant, the reported cases in the literature, and the variant's rarity, the p.Leu1997MetfsTer60 variant is classified as pathogenic for SPG11-related spastic paraplegia. - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 03-05-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at