rs312262759
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.4307_4308del(p.Gln1436ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,168 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. Q1436Q) 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.4307_4308del | p.Gln1436ArgfsTer7 | frameshift_variant | 25/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.4307_4308del | p.Gln1436ArgfsTer7 | frameshift_variant | 25/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251420Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135874
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461882Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 727244
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152286Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74454
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, no assertion criteria provided | research | Section for Clinical Neurogenetics, University of Tübingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 25, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift deletion p.Q1436Rfs*7 in SPG11 (NM_025137.4) has been reported to ClinVar as Pathogenic. This variant has been observed in individuals affected with autosomal recessive hereditary spastic paraplegia and to segregate with disease in a family (Stevanin G et al, 2008; Novarino G et al, 2014). The p.Q1436Rfs*7 variant is observed in 1/16,256 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 7 residues until a stop codon is reached. The gene SPG11 has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 3.29. The p.Q1436Rfs*7 variant is a loss of function variant in the gene SPG11, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_079413.3:p.L68Ffs*2 and 156 others. There are 83 downstream pathogenic loss of function variants, with the furthest variant being 952 residues downstream of the variant p.Q1436Rfs*7. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 10, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Gln1436Argfs*7) 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 (rs312262759, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 18079167, 24482476). 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. ClinVar contains an entry for this variant (Variation ID: 41315). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18586399, 30081747, 19105190, 24482476, 29980238, 26374131, 24833714, 18079167, 31589614, 32214227, 33098801, 33619735, 35872528) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 28, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2022 | The c.4307_4308delAA (p.Q1436Rfs*7) alteration, located in exon 25 (coding exon 25) of the SPG11 gene, consists of a deletion of 2 nucleotides from position 4307 to 4308, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.4307_4308delAA (p.Q1436Rfs*7) alteration has an overall frequency of 0.004% (10/282800) total alleles studied. The highest observed frequency was 0.012% (3/24962) of African alleles. This alteration has been detected in the homozygous state or in conjunction with a second disease-causing allele in multiple individuals with SPG11-related neurologic disorders (Stevanin, 2008; Lynch, 2016; Pensato, 2014; Denora, 2009; Chen, 2008; Hengel 2020; Zech 2020; Shi 2022; Utz 2022; Dosi, 2021). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at