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

Genomes: not found (cov: 32)

Consequence

KIF5A
NM_004984.4 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.86
Variant links:
Genes affected
KIF5A (HGNC:6323): (kinesin family member 5A) This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a region_of_interest Microtubule-binding (size 141) in uniprot entity KIF5A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_004984.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the KIF5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 3.5984 (above the threshold of 3.09). Trascript score misZ: 5.0239 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis, susceptibility to, 25, inherited neurodegenerative disorder, hereditary spastic paraplegia 10, myoclonus, intractable, neonatal, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF5ANM_004984.4 linkc.857G>C p.Arg286Thr missense_variant Exon 10 of 29 ENST00000455537.7 NP_004975.2 Q12840
KIF5ANM_001354705.2 linkc.590G>C p.Arg197Thr missense_variant Exon 7 of 26 NP_001341634.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF5AENST00000455537.7 linkc.857G>C p.Arg286Thr missense_variant Exon 10 of 29 1 NM_004984.4 ENSP00000408979.2 Q12840

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia Pathogenic:1
Nov 04, 2024
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
May 15, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.93
D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.6
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.80
Gain of catalytic residue at K283 (P = 0.001);.;
MVP
0.94
MPC
3.2
ClinPred
1.0
D
GERP RS
4.2
Varity_R
0.96
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1224640834; hg19: chr12-57963076; API