12-57569293-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_004984.4(KIF5A):c.857G>C(p.Arg286Thr) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004984.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia Pathogenic:1
This sequence change in KIF5A is predicted to replace arginine with threonine at codon 286, p.(Arg286Thr). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the kinesin motor domain a region (amino acids 44-327) defined as a mutational hotspot hereditary spastic paraplegia (HSP) and Charcot-Marie Tooth associated missense variants (PMID: 25008398). There is a moderate physicochemical difference between arginine and threonine. This variant is absent from the population database gnomAD v4.1. This variant has been detected in at least two probands with hereditary spastic paraplegia (HSP) (Labcorp genetics (formerly Invitae); Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.91) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PP3_Moderate, PS4_Supporting. -
Spastic paraplegia Uncertain:1
This sequence change replaces arginine with threonine at codon 286 of the KIF5A protein (p.Arg286Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KIF5A-related disease. 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. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at