12-57569403-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_004984.4(KIF5A):c.967C>T(p.Arg323Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KIF5A
NM_004984.4 missense, splice_region

Scores

Splicing: ADA: 0.9964

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 0.343

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 12-57569403-C-T is Pathogenic according to our data. Variant chr12-57569403-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409666.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=4}. Variant chr12-57569403-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4 link	c.967C>T	p.Arg323Trp	missense_variant, splice_region_variant	Exon 10 of 29	ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	c.700C>T	p.Arg234Trp	missense_variant, splice_region_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.967C>T	p.Arg323Trp	missense_variant, splice_region_variant	Exon 10 of 29	1	NM_004984.4	ENSP00000408979.2		Q12840

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 10

Pathogenic:3

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism, and dominant negative is a likely mechanism of disease in this gene and is associated with myoclonus, intractable, neonatal (NEIMY; MIM#617235) and spastic paraplegia 10 (SPG10; MIM#604187). Missense variants have been described in individuals with SPG10, whereas truncating variants in the last exon, or those resulting in protein elongation, have been reported in NEIMY cases (PMIDs: 18203753, 27463701, 28678816). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinesin motor domain (DECIPHER). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Arg323Gln) has been classified as likely pathogenic and a VUS by clinical laboratories in ClinVar and has been observed in an individual with spastic paraplegia in the literature (PMID: 37926714). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and a VUS by multiple clinical laboratories in ClinVar. It has also been observed in three individuals with spastic paraplegia in the literature, one of which was de novo, and another co-segregated in the probands affected child (PMIDs: 34715294, 25695920, 31403080). (SP) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Paris Brain Institute, Inserm - ICM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was detected in a patient with axonal neuropathy. While the KIF5A gene is associated with spastic paraplegia, the c.967C>T variant has been reported to cause both spastic paraplegia and axonal neuropathy in multiple individuals. The variant is detected in control population database at a very low frequency (VAF 0.0001%, gnomAD v4.1.0). The variant is located within the kinesin motor domain (IPR001752). A different amino acid change at the same residue has been reported as likely pathogenic/variant of uncertain significance (CilnVar accession VCV001406446.7). In silico analysis suggests the variant to be pathogenic (REVEL 0.92). -

not provided

Pathogenic:3

Jan 26, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals, including a de novo case, with clinical features associated with this gene. Computational tools yielded predictions that this variant may interfere with normal RNA splicing. -

Spastic paraplegia

Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 323 of the KIF5A protein (p.Arg323Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with KIF5A-related conditions (PMID: 25695920, 31403080, 34715294, 34983064; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 409666). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia

Uncertain:1

Apr 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

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

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.82

Loss of disorder (P = 0.0135);.;

MVP

0.95

MPC

2.6

ClinPred

1.0

GERP RS

3.3

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.17

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