rs312262720
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.733_734del(p.Met245ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000071 ( 0 hom. )
Consequence
SPG11
NM_025137.4 frameshift
NM_025137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.17
Genes affected
SPG11 (HGNC:11226): (SPG11 vesicle trafficking associated, spatacsin) The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 15-44657229-CAT-C is Pathogenic according to our data. Variant chr15-44657229-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-44657229-CAT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.733_734del | p.Met245ValfsTer2 | frameshift_variant | 4/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.733_734del | p.Met245ValfsTer2 | frameshift_variant | 4/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251452Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135906
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GnomAD4 exome AF: 0.0000711 AC: 104AN: 1461870Hom.: 0 AF XY: 0.0000646 AC XY: 47AN XY: 727234
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:9Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 01, 2018 | The observed variant c.733_734delAT (p.M245Vfs) is not reported in The 1000 Genomes database and its minor allele frequency in ExAC database is 0.0001071. The in silico prediction for the variant is pathogenic by MutationTaster2. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Met245Valfs*2) 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 (rs312262720, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC and juvenile amyotrophic lateral sclerosis (PMID: 17322883, 17717710, 18067136, 18079167, 18332254, 18835492, 19105190, 19438933, 20110243, 22175763, 22237444, 22696581, 24833714, 27071356). ClinVar contains an entry for this variant (Variation ID: 1112). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Met245ValfsTer2 variant in SPG11 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in two siblings with spastic paraplegia. The presence of this variant in combination with a reported pathogenic variant and in an individual with spastic paraplegia increases the likelihood that the p.Met245ValfsTer2 variant is pathogenic. The p.Met245ValfsTer2 variant in SPG11 has been well-reported in the literature. This variant has been reported in greater than 22 individuals from Italy, Japan, France, Tunisia, Sicily, Korea, Spain, China, and Portugal with spastic paraplegia in the homozygous and compound heterozygous state, segregated with disease in 12 affected relatives from 5 families (PMID: 17717710, 20110243, 17322883, 18079167, 22175763, 18332254, 24833714, 22696581, 22237444, 18067136, 18835492), but has been identified in 0.006133% (17/277208) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs312262720). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1112). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 245 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive spastic paraplegia. In summary, the p.Met245ValfsTer2variant is pathogenic based off of our findings, multiple reports of pathogenicity in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1, PM3, PP1_Moderate (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift deletion p.M245Vfs*2 in SPG11 (NM_025137.4) has been previously reported in many individuals affected with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC (Stevanin et al, 2007;Del Bo et al. 2007). This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 2 residues until a stop codon is reached. The p.M245Vfs*2 variant is a loss of function variant in the gene SPG11, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Hereditary spastic paraplegia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde | Mar 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 11, 2022 | Variant summary: SPG11 c.733_734delAT (p.Met245ValfsX2) 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 are associated with Spastic Paraplegia in HGMD. The variant allele was found at a frequency of 6.8e-05 in 251452 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (6.8e-05 vs 0.0011). c.733_734delAT has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia (examples: Boukhris_2009 and Stevanin_2008). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Charcot-Marie-Tooth disease axonal type 2X Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Abnormal central motor function Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2020 | The c.733_734delAT (p.M245Vfs*2) alteration, located in coding exon 4 of the SPG11 gene, results from a deletion of 2 nucleotides from position 733 to 734, causing a translational frameshift with a predicted alternate stop codon after 2 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 the Genome Aggregation Database (gnomAD), the c.733_734delAT alteration was observed in 0.006% (18/282852) of total alleles studied. In multiple individuals with spastic paraplegia with thin corpus callosum, this alteration has been detected in the homozygous state or in conjunction with a second disease-causing allele (Stevanin, 2007; Boukhris, 2008; Pensato, 2014; Dong, 2018; Wei, 2019). This alteration was also identified in a patient meeting diagnostic criteria for amyotrophic lateral sclerosis (ALS) and a brain MRI which was negative for thin corpus callosum and white matter abnormalities; this individual was also heterozygous for a nonsense variant in SPG11 (Orlacchio, 2010). Based on the available evidence, this alteration is classified as pathogenic. - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5;C5569024:Charcot-Marie-Tooth disease axonal type 2X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 05, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2021 | 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17717710, 18332254, 20110243, 22175763, 17322883, 18067136, 27071356, 31227335, 31289639, 31969655, 29980238, 31589614) - |
Amyotrophic lateral sclerosis type 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2010 | - - |
Hereditary spastic paraplegia 11;C1865864:Amyotrophic lateral sclerosis type 5 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 05-07-2018 by 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
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Details are displayed if max score is > 0.2
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