rs147713329
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025137.4(SPG11):c.6091C>T(p.Arg2031Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,886 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SPG11
NM_025137.4 stop_gained
NM_025137.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.759
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-44573661-G-A is Pathogenic according to our data. Variant chr15-44573661-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SPG11 | NM_025137.4 | c.6091C>T | p.Arg2031Ter | stop_gained | 32/40 | ENST00000261866.12 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPG11 | ENST00000261866.12 | c.6091C>T | p.Arg2031Ter | stop_gained | 32/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461886Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727244
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GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 11 Pathogenic:4Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained variant c.6091C>T (p.Arg2031Ter) in the SPG11 gene has been reported in the compound heterozygous and homozygous state in individuals affected with hereditary spastic paraplegia (Travaglini et al., 2018; Kara et al., 2016). The variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic (Multiple submitters). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg2031*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 18408091, 29691679). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41340). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000041340, PMID:18408091). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 13, 2022 | This variant is expected to result in the loss of a functional protein. This variant segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Reported in several members of one family with hereditary spastic paraplegia who also harbor a frameshift variant on the opposite allele (in trans) (Lee et al., 2008); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31227335, 31692161, 29691679, 18408091) - |
Hereditary spastic paraplegia Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2023 | Variant summary: SPG11 c.6091C>T (p.Arg2031X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251360 control chromosomes (gnomAD). c.6091C>T has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia, Type 11 (e.g. Denora_2009). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 19105190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Amyotrophic lateral sclerosis type 5 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 18408091, 29691679, 25525159] - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at