rs1553318274
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_014946.4(SPAST):c.1412G>A(p.Gly471Asp) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G471C) has been classified as Uncertain significance.
Frequency
Consequence
NM_014946.4 missense, splice_region
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.1412G>A | p.Gly471Asp | missense_variant, splice_region_variant | 11/17 | ENST00000315285.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1412G>A | p.Gly471Asp | missense_variant, splice_region_variant | 11/17 | 1 | NM_014946.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2017 | This sequence change replaces glycine with aspartic acid at codon 471 of the SPAST protein (p.Gly471Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo and segregate with disease in a family affected with hereditary spastic paraplegia (HSP) (PMID: 17560499). It has also been reported in an unrelated individual affected with HSP (PMID: 26671083). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at