rs375693647

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 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 5 ACMG points.

• PM1: In a region_of_interest Microtubule-binding (size 141) in uniprot entity KIF5A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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.

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

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;