12-57576326-C-T

Position:

chr12-57576326-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_004984.4(KIF5A):c.2146C>T(p.Arg716Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

KIF5A
NM_004984.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.862

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 links:

KIF5A (HGNC:):

KIF5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF5A. . Gene score misZ 3.5984 (greater than the threshold 3.09). Trascript score misZ 5.0239 (greater than threshold 3.09). GenCC has associacion of gene with 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.

BP6

Variant 12-57576326-C-T is Benign according to our data. Variant chr12-57576326-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409667.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF5A	NM_004984.4 linkuse as main transcript	c.2146C>T	p.Arg716Trp	missense_variant	19/29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 linkuse as main transcript	c.1879C>T	p.Arg627Trp	missense_variant	16/26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7 linkuse as main transcript	c.2146C>T	p.Arg716Trp	missense_variant	19/29	1	NM_004984.4	ENSP00000408979.2		Q12840

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250718

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

KIF5A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The KIF5A c.2146C>T variant is predicted to result in the amino acid substitution p.Arg716Trp. This variant was reported in an individual with spastic paraplegia and was interpreted as uncertain (Table 3, Iqbal et al. 2017. PubMed ID: 28362824). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. A different missense change impacting the same amino acid (p.Arg716Gln) has been reported in two individuals with amyotrophic lateral sclerosis (Nakamura et al. 2021. PubMed ID: 32888732). At this time, the clinical significance of the c.2146C>T (p.Arg716Trp) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Amyotrophic lateral sclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Jan 01, 2022

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.74

MVP

0.64

MPC

1.7

ClinPred

0.53

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over