rs121918358
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_003119.4(SPG7):c.233T>A(p.Leu78*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,200 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 5 hom. )
Consequence
SPG7
NM_003119.4 stop_gained
NM_003119.4 stop_gained
Scores
7
Clinical Significance
Conservation
PhyloP100: 0.782
Genes affected
SPG7 (HGNC:11237): (SPG7 matrix AAA peptidase subunit, paraplegin) This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 16-89510539-T-A is Pathogenic according to our data. Variant chr16-89510539-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89510539-T-A is described in Lovd as [Pathogenic]. Variant chr16-89510539-T-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SPG7 | NM_003119.4 | c.233T>A | p.Leu78* | stop_gained | 2/17 | ENST00000645818.2 | NP_003110.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SPG7 | ENST00000645818.2 | c.233T>A | p.Leu78* | stop_gained | 2/17 | NM_003119.4 | ENSP00000495795.2 |
Frequencies
GnomAD3 genomes 0.000191 AC: 29AN: 152074Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000418 AC: 105AN: 251260Hom.: 2 AF XY: 0.000589 AC XY: 80AN XY: 135852
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GnomAD4 exome AF: 0.000278 AC: 406AN: 1461008Hom.: 5 Cov.: 34 AF XY: 0.000355 AC XY: 258AN XY: 726850
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GnomAD4 genome 0.000197 AC: 30AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74438
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:15
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2024 | Variant summary: SPG7 c.233T>A (p.Leu78X) 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. The variant allele was found at a frequency of 0.00042 in 251260 control chromosomes in the gnomAD database, including 2 homozygotes. c.233T>A has been reported in the literature in multiple homozygous individuals affected with Hereditary Spastic Paraplegia (e.g. Arnoldi_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating enzyme activity in homozygous patient fibroblasts with varied results between patients (e.g. Arnoldi_2008). The most pronounced variant effect results in 30%-50% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 18200586). ClinVar contains an entry for this variant (Variation ID: 6816). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research | Jan 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | The observed missense variant c.233T>Ap.Leu78Ter in SPG7 gene has been reported in homozygous/compound heterozygous state in multiple individuals with Ataxia/Hereditary Spastic Paraplegia 7 Perić S, et al., 2022, Hewamadduma CA, et al., 2018. The p.Leu78Ter variant has 0.04% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Uncertain Significance/Likely Pathogenic/ Pathogenic multiple submissions. The nucleotide change c.233T>A in SPG7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence Mutation Taster - Disease causing predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 08, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO:0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 108 heterozygotes, 2 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous and homozygous individuals with spastic paraplegia (ClinVar, PMIDs: 23065789, 36139378). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 16, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 07, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2008 | - - |
| Pathogenic, criteria provided, single submitter | case-control | Neurogenetics of motion laboratory, Montreal Neurological Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2023 | This sequence change creates a premature translational stop signal (p.Leu78*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs121918358, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive hereditary spastic paraplegia (PMID: 18200586, 22571692, 24727571). 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: 6816). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 24, 2021 | This variant was identified as compound heterozygous with NM_003119.4:c.1529C>T. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 20, 2021 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | SPG7: PM3:Very Strong, PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 05, 2024 | 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 multiple unrelated individuals with clinical features associated with this gene. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2022 | 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; This variant is associated with the following publications: (PMID: 25525159, 27084228, 28362824, 29482223, 18200586, 23065789, 22571692, 26626314, 22964162, 25681447, 25976027, 31433872, 31407473, 33300680, 31589614, 33084218, 33624863) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Hereditary spastic paraplegia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2021 | - - |
SPG7-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 30, 2024 | The SPG7 c.233T>A variant is predicted to result in premature protein termination (p.Leu78*). This variant has been reported in the homozygous state in individuals with hereditary spastic paraplegia (Arnoldi et al. 2008. PubMed ID: 18200586; Iqbal et al. 2017. PubMed ID: 28362824). In addition, one study suggested that this variant may act in a dominant fashion, although no evidence was provided to support this claim beyond segregation of the variant with the disease in the family (Sánchez-Ferrero et al. 2013. PubMed ID: 22571692). This variant is reported in 0.28% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Retinal dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
Proximal spinal muscular atrophy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 26, 2018 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
0.87, 0.88
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at