chr16-89530793-TGTGGATTATCTGAAG-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong
The NM_003119.4(SPG7):c.976_987+3del variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
SPG7
NM_003119.4 inframe_deletion, splice_region
NM_003119.4 inframe_deletion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.90
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 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_003119.4.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 16-89530793-TGTGGATTATCTGAAG-T is Pathogenic according to our data. Variant chr16-89530793-TGTGGATTATCTGAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG7 | NM_003119.4 | c.976_987+3del | inframe_deletion, splice_region_variant | 7/17 | ENST00000645818.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG7 | ENST00000645818.2 | c.976_987+3del | inframe_deletion, splice_region_variant | 7/17 | NM_003119.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 30, 2017 | - - |
Hereditary spastic paraplegia 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). ClinVar contains an entry for this variant (Variation ID: 239501). This variant, c.973_987del, results in the deletion of 5 amino acids of the SPG7 protein (p.Val325_Lys329del), but otherwise preserves the integrity of the reading frame. This variant also impacts the last nucleotide of exon 7 of the SPG7 coding sequence, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at