rs587777757
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_014946.4(SPAST):āc.1216A>Gā(p.Ile406Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,338 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 (ā ā ).
Frequency
Consequence
NM_014946.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460338Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 726588
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:4
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 406 of the SPAST protein (p.Ile406Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia and was observed to be de novo in at least one individual (PMID: 16476945, 16682546, 16832076, 17971434, 18701882, 19423133). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPAST protein function with a negative predictive value of 80%. 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. -
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not provided Pathogenic:2
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant resulted in a 30-bp deletion when expressed in a cell line. However, only 20% of transcript was affected and it is unclear if this is sufficient aberrant transcript to cause disease (PMID 16476945). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -
Identified in patients with HSP in published literature, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members (PMID: 16682546, 19423133, 20562464); Published functional studies demonstrate damaging effects, including aberrant in-frame splicing, destabilization of mutated transcript, and deficient in microtubule-severing activity (PMID: 16476945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30476002, 16832076, 20562464, 19423133, 16476945, 31157359, 16055926, 34758253, 21139634, 26094131, 31594988, 34983064, 16682546) -
Hereditary spastic paraplegia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at