NM_004984.4:c.750C>G

Variant names:

• chr12-57568998-C-G
• rs375693647
• NM_004984.4:c.750C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

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. Synonymous variant affecting the same amino acid position (i.e. D250D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.680
• Publications: 0 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: ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• inherited neurodegenerative disorder

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004984.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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;.
PhyloP100		-0.68
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
Mutation Taster		=42/58	disease causing

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: rs375693647; hg19: chr12-57962781;