rs387907287

Variant names:

• chr12-57567515-G-A
• rs387907287
• NM_004984.4:c.611G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57567515-G-A
• chr12-57567515-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004984.4(KIF5A):​c.611G>A​(p.Arg204Gln) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003921589: Published functional studies demonstrate a damaging effect on ATPase rate and microtubule affinity, resulting in abnormal microtubule motility (Jennings et al., 2017)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 28)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.90
• Publications: 11 publications found

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]

KIF5A Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis, susceptibility to, 25

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
• inherited neurodegenerative disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myoclonus, intractable, neonatal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia 10

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003921589: Published functional studies demonstrate a damaging effect on ATPase rate and microtubule affinity, resulting in abnormal microtubule motility (Jennings et al., 2017); PMID: 24731568, 26543653, 25008398, 27066564, 21107874, 21623771, 32319259, 22785106, 28678816, 18853458; SCV002766278: The most pronounced variant effect results in <10% of normal mictotubule-stimulated ATPase activity and reduced microtubule affinity. Jennings_2017
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr12-57567514-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 12-57567515-G-A is Pathogenic according to our data. Variant chr12-57567515-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004984.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	NM_004984.4	MANE Select	c.611G>A	p.Arg204Gln	missense	Exon 8 of 29	NP_004975.2
	KIF5A	NM_001354705.2		c.344G>A	p.Arg115Gln	missense	Exon 5 of 26	NP_001341634.1	J3KNA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	ENST00000455537.7	TSL:1 MANE Select	c.611G>A	p.Arg204Gln	missense	Exon 8 of 29	ENSP00000408979.2	Q12840
	KIF5A	ENST00000674619.1		c.611G>A	p.Arg204Gln	missense	Exon 8 of 30	ENSP00000502270.1	A0A6Q8PGJ3
	KIF5A	ENST00000938849.1		c.611G>A	p.Arg204Gln	missense	Exon 8 of 28	ENSP00000608908.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

Alfa AF: 0.00000494 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Hereditary spastic paraplegia 10 (4)
2	-	-	KIF5A-related disorder (2)
2	-	-	Myoclonus, intractable, neonatal (2)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Gain of catalytic residue at H201 (P = 0.0021)
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.89
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907287; hg19: chr12-57961298;