rs121434443
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_004984.4(KIF5A):c.827A>G(p.Tyr276Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y276H) has been classified as Uncertain significance.
Frequency
Consequence
NM_004984.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF5A | NM_004984.4 | c.827A>G | p.Tyr276Cys | missense_variant | 10/29 | ENST00000455537.7 | |
KIF5A | NM_001354705.2 | c.560A>G | p.Tyr187Cys | missense_variant | 7/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF5A | ENST00000455537.7 | c.827A>G | p.Tyr276Cys | missense_variant | 10/29 | 1 | NM_004984.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2022 | ClinVar contains an entry for this variant (Variation ID: 6808). 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 KIF5A protein function. This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 16489470; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 276 of the KIF5A protein (p.Tyr276Cys). - |
Hereditary spastic paraplegia 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 18, 2018 | Not found in the total gnomAD dataset, and the data is high quality (0/277086 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Strong co-segregation with disease. However, available data are from a single family. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at