rs143326964

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004984.4(KIF5A):c.1150G>C(p.Gly384Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,613,702 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. G384E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 3 hom. )

Consequence

KIF5A
NM_004984.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 1.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant where missense usually causes diseases, KIF5A

BP4

Computational evidence support a benign effect (MetaRNN=0.026566148).

BP6

Variant 12-57570019-G-C is Benign according to our data. Variant chr12-57570019-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287325.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=7}. Variant chr12-57570019-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000643 (98/152376) while in subpopulation AMR AF= 0.00333 (51/15310). AF 95% confidence interval is 0.0026. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4 linkuse as main transcript	c.1150G>C	p.Gly384Arg	missense_variant	12/29	ENST00000455537.7
KIF5A	NM_001354705.2 linkuse as main transcript	c.883G>C	p.Gly295Arg	missense_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7 linkuse as main transcript	c.1150G>C	p.Gly384Arg	missense_variant	12/29	1	NM_004984.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000447

AC:

112

AN:

250768

Hom.:

AF XY:

0.000487

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.000465

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000507

AC:

741

AN:

1461326

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000928

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000519

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000643

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000379

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	KIF5A: BS1 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.1150G>C (p.G384R) alteration is located in exon 12 (coding exon 12) of the KIF5A gene. This alteration results from a G to C substitution at nucleotide position 1150, causing the glycine (G) at amino acid position 384 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2017

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 14, 2016

- -

KIF5A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.026

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.55

N;.

MutationTaster

Benign

0.68

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.74

N;N

REVEL

Benign

0.20

Sift

Benign

0.48

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0040

B;.

Vest4

0.40

MutPred

0.25

Gain of solvent accessibility (P = 0.0674);.;

MVP

0.35

MPC

0.75

ClinPred

0.027

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.58

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