rs121434442

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004984.4(KIF5A):c.838C>T(p.Arg280Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. R280L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KIF5A
NM_004984.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.12

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a mutagenesis_site Strongly reduces microtubule affinity; slightly reduces gliding velocity. (size 0) in uniprot entity KIF5A_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP2

Missense variant in the KIF5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 3.5984 (above the threshold of 3.09). Trascript score misZ: 5.0239 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 12-57569274-C-T is Pathogenic according to our data. Variant chr12-57569274-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6807.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.838C>T	p.Arg280Cys	missense_variant	Exon 10 of 29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	c.571C>T	p.Arg191Cys	missense_variant	Exon 7 of 26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 10 of 29	1	NM_004984.4	ENSP00000408979.2		Q12840

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Sep 26, 2022

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant appears to segregate with spastic paraplegia in at least one family. Functional studies showed that mutant proteins have reduced microtubule affinity but still possess the regulatory mechanisms (PMID: 18203753). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 10

Pathogenic:2

Aug 12, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia

Pathogenic:1

Dec 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg280 amino acid residue in KIF5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18853458, 25008398, 28832565, 29892902). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KIF5A function (PMID: 18203753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6807). This missense change has been observed in individuals with KIF5A-related conditions (PMID: 15452312, 25008398, 31211173; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the KIF5A protein (p.Arg280Cys). -

Hereditary spastic paraplegia

Pathogenic:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.93

MutPred

0.87

Gain of catalytic residue at K283 (P = 2e-04);.;

MVP

0.98

MPC

3.0

ClinPred

1.0

GERP RS

4.2

Varity_R

0.92

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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