rs1131691838
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_014946.4(SPAST):c.1334G>A(p.Ser445Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S445R) has been classified as Pathogenic.
Frequency
Consequence
NM_014946.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPAST | NM_014946.4 | c.1334G>A | p.Ser445Asn | missense_variant | 11/17 | ENST00000315285.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1334G>A | p.Ser445Asn | missense_variant | 11/17 | 1 | NM_014946.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2018 | Other missense substitutions at this codon (p.Ser445Arg and p.Ser445Thr) have been reported in individuals affected with hereditary spastic paraplegia (PMID: 16832076, 26086985). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with hereditary spastic paraplegia (PMID: 20562464). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 445 of the SPAST protein (p.Ser445Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at