12-57568999-G-A

Position:

• chr12-57568999-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004984.4(KIF5A):​c.751G>A​(p.Glu251Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E251D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 19 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, 5 uncertain in NM_004984.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57569001-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1711347.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.971
• PP5: Variant 12-57568999-G-A is Pathogenic according to our data. Variant chr12-57568999-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57568999-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.751G>A	p.Glu251Lys	missense_variant	9/29	ENST00000455537.7
KIF5A	NM_001354705.2	c.484G>A	p.Glu162Lys	missense_variant	6/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.751G>A	p.Glu251Lys	missense_variant	9/29	1	NM_004984.4	P1
KIF5A	ENST00000674619.1	c.751G>A	p.Glu251Lys	missense_variant	9/30
KIF5A	ENST00000676457.1	c.646G>A	p.Glu216Lys	missense_variant	8/28
KIF5A	ENST00000286452.5	c.484G>A	p.Glu162Lys	missense_variant	6/26	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 10 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 22, 2018	The KIF5A c.751G>A; p.Glu251Lys variant (rs387907285) has been reported in the heterozygous state in at least six individuals from three families diagnosed with hereditary spastic paraplegia (Goizet 2009, Iqbal 2017, Neveling 2013), as well as a family member diagnosed with CMT (Goizet 2009). The affected amino acid is in a functionally important region of the protein’s head domain, and variants affecting nearby amino acids have been classified as pathogenic (Crimella 2012, Lynch 2016, Schule 2008). Functional studies of the homologous Drosophila gene showed that mutations in this region result in reduced mitochondrial and dense core vesicle flux within larval axons (Djagaeva 2012). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), and is listed as pathogenic in ClinVar (ID 37127). Based on the available information, the p.Glu251Lys variant is classified as pathogenic. -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 251 of the KIF5A protein (p.Glu251Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spastic paraplegia (PMID: 18853458, 24123792, 28362824). ClinVar contains an entry for this variant (Variation ID: 37127). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KIF5A function (PMID: 22714410). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.84		Gain of MoRF binding (P = 0.0106);.;
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.99

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

Other links and lift over

dbSNP: rs387907285; hg19: chr12-57962782;