rs148175530
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_025137.4(SPG11):c.491C>T(p.Ser164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S164P) has been classified as Uncertain significance.
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.491C>T | p.Ser164Leu | missense_variant | 3/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.491C>T | p.Ser164Leu | missense_variant | 3/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000426 AC: 107AN: 251368Hom.: 0 AF XY: 0.000405 AC XY: 55AN XY: 135886
GnomAD4 exome AF: 0.000226 AC: 331AN: 1461726Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160AN XY: 727178
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74494
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 11, 2022 | Variant summary: SPG11 c.491C>T (p.Ser164Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251368 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (0.00043 vs 0.0011), allowing no conclusion about variant significance. c.491C>T has been reported in the literature as a VUS and/or without sufficient evidence among cohorts of individuals with Amyotrophic Lateral Sclerosis (ALS)/Multiple Sclerosis (MS) undergoing multigene panel testing/chip based genotyping/whole genome sequencing (WGS) (example, Ghani_2015, Jung Kim_2016, Jia_2018, Chen_2020, McCann_2020). At-least one of these reports included a homozygous proband with sporadic ALS (example, McCann_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Hereditary Spastic Paraplegia, Type 11. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 24, 2021 | Reported previously in patients with Alzheimer disease and sporadic ALS who also harbored a second SPG11 variant; however, additional clinical and segregation information were not provided (Ghani et al., 2015; Chen et al., 2020); Reported previously in the homozygous state in a patient with sporadic ALS and not seen in control samples; however, further clinical and segregation information were not provided (McCann et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26556829, 25174650, 32166880, 32409511) - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hereditary spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 21, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at