chr12-57567514-C-G

Position:

• chr12-57567514-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_004984.4(KIF5A):​c.610C>G​(p.Arg204Gly) 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 pathogenic 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. R204Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 28)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57567515-G-A is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.610C>G	p.Arg204Gly	missense_variant	8/29	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.343C>G	p.Arg115Gly	missense_variant	5/26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.610C>G	p.Arg204Gly	missense_variant	8/29	1	NM_004984.4	ENSP00000408979	P1
KIF5A	ENST00000674619.1	c.610C>G	p.Arg204Gly	missense_variant	8/30			ENSP00000502270
KIF5A	ENST00000676457.1	c.505C>G	p.Arg169Gly	missense_variant	7/28			ENSP00000501588
KIF5A	ENST00000286452.5	c.343C>G	p.Arg115Gly	missense_variant	5/26	2		ENSP00000286452

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

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	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at H201 (P = 8e-04);.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555177629; hg19: chr12-57961297; COSMIC: COSV54052618;