rs786204057
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_014946.4(SPAST):c.1637G>A(p.Gly546Glu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G546R) has been classified as Pathogenic.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPAST | NM_014946.4 | c.1637G>A | p.Gly546Glu | missense_variant | 15/17 | ENST00000315285.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1637G>A | p.Gly546Glu | missense_variant | 15/17 | 1 | NM_014946.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2018 | This missense change is located within a functionally conserved AAA domain of the SPAST protein (PMID: 9695811, 18410514) and a high percentage (~85%) of previously reported SPAST missense mutations have been found within this domain (PMID: 18701882). These observations suggest that a novel missense substitution within this domain may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Gly546Glu and p.Gly546Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 27260292, Invitae). This variant has been observed to be de novo in an individual affected with hereditary spastic paraplegia (PMID: Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 546 of the SPAST protein (p.Gly546Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at