dbSNP rs375693647: KIF5A:p.Asp250Glu (chr12-57568998-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.680

Publications

0 publications found

Variant links:

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

KIF5A links:

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ACMG classification

Classification was made for transcript

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 link	c.750C>G	p.Asp250Glu	missense_variant	Exon 9 of 29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	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	UniProt
KIF5A	ENST00000455537.7 link	c.750C>G	p.Asp250Glu	missense_variant	Exon 9 of 29	1	NM_004984.4	ENSP00000408979.2	Q12840
KIF5A	ENST00000674619.1 link	c.750C>G	p.Asp250Glu	missense_variant	Exon 9 of 30			ENSP00000502270.1	A0A6Q8PGJ3
KIF5A	ENST00000676457.1 link	c.645C>G	p.Asp215Glu	missense_variant	Exon 8 of 28			ENSP00000501588.1	A0A6Q8PEZ8
KIF5A	ENST00000286452.5 link	c.483C>G	p.Asp161Glu	missense_variant	Exon 6 of 26	2		ENSP00000286452.5	J3KNA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.23

CADD

Benign

1.6

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.76

D;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-1.0

N;.

PhyloP100

-0.68

PrimateAI

Pathogenic

0.85

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

GERP RS

-8.5

Varity_R

0.34

gMVP

0.92

Mutation Taster

=42/58

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over