rs375693647

Positions:

• chr12-57568998-C-G
• chr12-57568998-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004984.4(KIF5A):​c.750C>G​(p.Asp250Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.680

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.750C>G	p.Asp250Glu	missense_variant	9/29	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.483C>G	p.Asp161Glu	missense_variant	6/26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.750C>G	p.Asp250Glu	missense_variant	9/29	1	NM_004984.4	ENSP00000408979.2
KIF5A	ENST00000674619.1	c.750C>G	p.Asp250Glu	missense_variant	9/30			ENSP00000502270.1
KIF5A	ENST00000676457.1	c.645C>G	p.Asp215Glu	missense_variant	8/28			ENSP00000501588.1
KIF5A	ENST00000286452.5	c.483C>G	p.Asp161Glu	missense_variant	6/26	2		ENSP00000286452.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	1.6
DANN	Benign	0.92
DEOGEN2	Uncertain	0.76	D;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-1.0	N;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.44	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.85	P;.
Vest4		0.67
MutPred		0.35		Gain of disorder (P = 0.0732);.;
MVP		0.76
MPC		2.3
ClinPred		0.69	D
GERP RS		-8.5
Varity_R		0.34
gMVP		0.92

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: rs375693647; hg19: chr12-57962781;