12-57581917-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004984.4(KIF5A):c.2957C>T(p.Pro986Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,014 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P986R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 10 hom., cov: 31)

Exomes 𝑓: 0.012 ( 136 hom. )

Consequence

KIF5A
NM_004984.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.25

Publications

24 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
inherited neurodegenerative disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
myoclonus, intractable, neonatal
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia 10
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040162504).

BP6

Variant 12-57581917-C-T is Benign according to our data. Variant chr12-57581917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240087.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00999 (1521/152194) while in subpopulation NFE AF = 0.0135 (919/68000). AF 95% confidence interval is 0.0128. There are 10 homozygotes in GnomAd4. There are 760 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1521 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004984.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	NM_004984.4	MANE Select	c.2957C>T	p.Pro986Leu	missense	Exon 26 of 29	NP_004975.2
	KIF5A	NM_001354705.2		c.2690C>T	p.Pro897Leu	missense	Exon 23 of 26	NP_001341634.1	J3KNA1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF5A	ENST00000455537.7	TSL:1 MANE Select	c.2957C>T	p.Pro986Leu	missense	Exon 26 of 29	ENSP00000408979.2	Q12840
KIF5A	ENST00000674619.1		c.2978C>T	p.Pro993Leu	missense	Exon 27 of 30	ENSP00000502270.1	A0A6Q8PGJ3
KIF5A	ENST00000938849.1		c.2957C>T	p.Pro986Leu	missense	Exon 26 of 28	ENSP00000608908.1

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1521

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00996

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0270

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.0110

AC:

2770

AN:

251490

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00425

Gnomad ASJ exome

AF:

0.00794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0305

Gnomad NFE exome

AF:

0.0149

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.0124

AC:

18173

AN:

1461820

Hom.:

136

Cov.:

AF XY:

0.0120

AC XY:

8728

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.00452

AC:

202

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00715

AC:

187

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00325

AC:

280

AN:

86256

European-Finnish (FIN)

AF:

0.0290

AC:

1548

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0137

AC:

15223

AN:

1111956

Other (OTH)

AF:

0.0110

AC:

665

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

954

1908

2861

3815

4769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

552

1104

1656

2208

2760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00999

AC:

1521

AN:

152194

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

760

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41518

American (AMR)

AF:

0.00994

AC:

152

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00352

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0270

AC:

286

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

919

AN:

68000

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00815

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0145

AC:

125

ExAC

AF:

0.0112

AC:

1357

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0132

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hereditary spastic paraplegia 10 (2)

Amyotrophic lateral sclerosis (1)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

2.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.30

REVEL

Benign

0.14

Sift

Uncertain

0.018

Sift4G

Uncertain

0.019

Polyphen

0.0

Vest4

0.21

MPC

0.64

ClinPred

0.0073

GERP RS

2.8

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.049

gMVP

0.71

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over