chr16-89553952-A-AT
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_003119.4(SPG7):c.2096dupT(p.Met699IlefsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
SPG7
NM_003119.4 frameshift
NM_003119.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.75
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 11 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 16-89553952-A-AT is Pathogenic according to our data. Variant chr16-89553952-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411678.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=7}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SPG7 | NM_003119.4 | c.2096dupT | p.Met699IlefsTer4 | frameshift_variant | Exon 15 of 17 | ENST00000645818.2 | NP_003110.1 | |
| SPG7 | NM_001363850.1 | c.2096dupT | p.Met699IlefsTer4 | frameshift_variant | Exon 15 of 18 | NP_001350779.1 | ||
| SPG7 | XM_047434537.1 | c.1223dupT | p.Met408IlefsTer4 | frameshift_variant | Exon 10 of 13 | XP_047290493.1 | ||
| SPG7 | XM_047434540.1 | c.782dupT | p.Met261IlefsTer4 | frameshift_variant | Exon 7 of 9 | XP_047290496.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000443 AC: 11AN: 248248Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134870
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GnomAD4 exome AF: 0.0000651 AC: 95AN: 1459236Hom.: 0 Cov.: 32 AF XY: 0.0000826 AC XY: 60AN XY: 725982
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GnomAD4 genome 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 7 Pathogenic:4Uncertain:1
| Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 12, 2024 | This sequence change creates a premature translational stop signal (p.Met699Ilefs*4) 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 (rs747503698, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. ClinVar contains an entry for this variant (Variation ID: 411678). For these reasons, this variant has been classified as Pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 11, 2018 | This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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 and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 13, 2024 | Variant summary: SPG7 c.2096dupT (p.Met699IlefsX4) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.4e-05 in 248248 control chromosomes, predominantly at a frequency of 9.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SPG7 causing Hereditary Spastic Paraplegia 7, allowing no conclusion about variant significance. c.2096dupT has been reported in the literature in unspecified individuals undertaking genetic testing, however not all the information was provided for further analysis (Stranneheim_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33726816). ClinVar contains an entry for this variant (Variation ID: 411678). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 05, 2024 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 30, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2025 | 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; This variant is associated with the following publications: (PMID: 34758253, 33726816, 37152446, 22571692, 31589614) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 09, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 30, 2018 | 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 at least one individual with clinical features associated with this gene. - |
SPG7-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | The SPG7 c.2096dupT variant is predicted to result in a frameshift and premature protein termination (p.Met699Ilefs*4). This variant has been reported in the literature; however, phenotypes of the individuals carrying this variant were not specified (Stranneheim et al. 2021. PubMed ID: 33726816; 100,000 Genomes Project Pilot Investigators et al. 2021. PubMed ID: 34758253). This variant is reported in 0.0095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SPG7 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
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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