rs140929639

Positions:

• chr12-57569671-C-G
• chr12-57569671-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004984.4(KIF5A):​c.1105C>G​(p.Arg369Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF5A. . Gene score misZ 3.5984 (greater than the threshold 3.09). Trascript score misZ 5.0239 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39274365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.1105C>G	p.Arg369Gly	missense_variant	11/29	ENST00000455537.7
KIF5A	NM_001354705.2	c.838C>G	p.Arg280Gly	missense_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.1105C>G	p.Arg369Gly	missense_variant	11/29	1	NM_004984.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.98	D;.
Vest4		0.40
MutPred		0.44		Loss of MoRF binding (P = 0.0193);.;
MVP		0.50
MPC		0.81
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs140929639; hg19: chr12-57963454;