chr2-32137145-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_014946.4(SPAST):c.1450G>C(p.Gly484Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G484D) has been classified as Uncertain significance.
Frequency
Consequence
NM_014946.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPAST | NM_014946.4 | c.1450G>C | p.Gly484Arg | missense_variant | 12/17 | ENST00000315285.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1450G>C | p.Gly484Arg | missense_variant | 12/17 | 1 | NM_014946.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2023 | This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 24731568; Invitae). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 448447). This missense change has been observed in at least one individual who was not affected with SPAST-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 484 of the SPAST protein (p.Gly484Arg). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21139634, 26094131, 24731568, 30476002) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at