rs1060502523

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_004984.4(KIF5A):c.3020G>A(p.Arg1007Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1007G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF5A
NM_004984.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.24

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-57582628-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 504479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-57582629-G-A is Pathogenic according to our data. Variant chr12-57582629-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 409669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4 link	c.3020G>A	p.Arg1007Lys	missense_variant, splice_region_variant	Exon 27 of 29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	c.2753G>A	p.Arg918Lys	missense_variant, splice_region_variant	Exon 24 of 26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7 link	c.3020G>A	p.Arg1007Lys	missense_variant, splice_region_variant	Exon 27 of 29	1	NM_004984.4	ENSP00000408979.2		Q12840

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251480

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725196

African (AFR)

AF:

0.00

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107568

Other (OTH)

AF:

0.00

AC:

AN:

60228

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Pathogenic:1

Dec 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1007 of the KIF5A protein (p.Arg1007Lys). This variant also falls at the last nucleotide of exon 27, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of amyotrophic lateral sclerosis (PMID: 29566793; Invitae). ClinVar contains an entry for this variant (Variation ID: 409669). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1

Jan 06, 2020

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant impacting the last nucleotide of the exon, immediately adjacent to the donor site, in a gene for which loss-of-function is a known mechanism of disease, and both in silico predictors and evolutionary conservation support a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29566793) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.55

N;.

PhyloP100

8.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.15

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.022

D;D

Sift4G

Benign

0.16

T;T

Polyphen

0.12

B;.

Vest4

0.38

MutPred

0.30

Gain of catalytic residue at P1011 (P = 0.0017);.;

MVP

0.85

MPC

1.5

ClinPred

0.62

GERP RS

5.5

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.31

gMVP

0.60

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.66

Position offset: 0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over