chr12-57569269-C-T

Variant names:

• chr12-57569269-C-T
• rs1555177824
• NM_004984.4:c.833C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004984.4(KIF5A):​c.833C>T​(p.Pro278Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P278S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.80

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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, 0.969
• PP5: Variant 12-57569269-C-T is Pathogenic according to our data. Variant chr12-57569269-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57569269-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.833C>T	p.Pro278Leu	missense_variant	Exon 10 of 29	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.566C>T	p.Pro189Leu	missense_variant	Exon 7 of 26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.833C>T	p.Pro278Leu	missense_variant	Exon 10 of 29	1	NM_004984.4	ENSP00000408979.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 10 Pathogenic:1

-

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Pathogenic:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.4	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.82		Gain of catalytic residue at K283 (P = 0.0025);.;
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555177824; hg19: chr12-57963052; COSMIC: COSV104591076;