rs765061840
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.1621C>T(p.Gln541Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,368 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
Consequence
NM_025137.4 stop_gained
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.1621C>T | p.Gln541Ter | stop_gained | 8/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.1621C>T | p.Gln541Ter | stop_gained | 8/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151920Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250478Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135504
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461448Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727010
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151920Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74188
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:3
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 20, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Gln541*) 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 (rs765061840, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or amyotrophic lateral sclerosis (PMID: 25299611, 28554332, 29246610). ClinVar contains an entry for this variant (Variation ID: 235891). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2022 | Reported previously in a patient with ALS, who also harbored the F2176L variant (reported as F2063L using alternative nomenclature); however segregation data was not provided (Couthouis et al., 2014); Reported previusly in a patient with complicated HSP who harbored 2 additional SPG11 variants; segregation analysis indicated that the F2176L variant and the Q541X variant were paternally inherited, and the other variant was maternally inherited (Burguez et al., 2017); Nonsense 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: 25299611, 28554332, 29246610) - |
Charcot-Marie-Tooth disease axonal type 2X Pathogenic:2
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Apr 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at