rs312262747
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.2716del(p.Gln906SerfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000041 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q906Q) 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.2716del | p.Gln906SerfsTer15 | frameshift_variant | 15/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.2716del | p.Gln906SerfsTer15 | frameshift_variant | 15/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135872
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727212
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change creates a premature translational stop signal (p.Gln906Serfs*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 (rs312262747, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 19105190, 26755014). ClinVar contains an entry for this variant (Variation ID: 41297). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote Frameshift variant c.2716delC in Exon 15 of the SPG11 gene that results in the amino acid substitution p.Gln906fs*15 was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 41297]. This variant is reported by Patel et al., 2016 for heredity Spastic Paraplegia. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 24, 2020 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 11, 2022 | - - |
Hereditary spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 17, 2023 | Variant summary: SPG11 c.2716delC (p.Gln906SerfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251404 control chromosomes (gnomAD). c.2716delC has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia (example: Denora_2009). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at