rs1553638086

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001244008.2(KIF1A):c.773C>T(p.Thr258Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. T258K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.69

Publications

4 publications found

Variant links:

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 9
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
PEHO syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001244008.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240783764-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1507070.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 2-240783764-G-A is Pathogenic according to our data. Variant chr2-240783764-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 464261.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
KIF1A	NM_001244008.2 link	c.773C>T	p.Thr258Met	missense_variant	Exon 8 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.773C>T	p.Thr258Met	missense_variant	Exon 8 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1431030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708762

African (AFR)

AF:

0.00

AC:

AN:

32820

American (AMR)

AF:

0.00

AC:

AN:

41062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25542

East Asian (EAS)

AF:

0.00

AC:

AN:

38146

South Asian (SAS)

AF:

0.00

AC:

AN:

81480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096828

Other (OTH)

AF:

0.00

AC:

AN:

59232

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 30

Pathogenic:5

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Paris Brain Institute, Inserm - ICM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2020

SIB Swiss Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); De novo (paternity and maternity confirmed) (PS2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). -

not provided

Pathogenic:3

Dec 12, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on selective binding to the GDP-bound lattice, motor activity, synaptic vesicle precursor delivery, and presynaptic strength in hippocampal neurons (PMID: 30612907, 28970574); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32045731, 28970574, 31488895, 32935419, 33880452, 37251230, 27535533, 37273706, 34983064, 34758253, 26125038, 21820098, 21376300, 30612907) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Apr 09, 2018

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Pathogenic:1

Nov 02, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuropathy, hereditary sensory, type 2C

Pathogenic:1

Oct 11, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 9

Pathogenic:1

Sep 16, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9

Pathogenic:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 258 of the KIF1A protein (p.Thr258Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HSP and hereditary spastic paraplegia (HSP) (PMID: 28970574; internal data). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464261). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KIF1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KIF1A function (PMID: 28970574). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;.;.;D;.;.;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.7

H;H;.;.;.;.;.;H;.;.;.;H;.

PhyloP100

9.7

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.8

.;D;D;.;.;.;.;.;.;.;.;D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

.;D;D;.;.;.;.;.;.;.;.;D;.

Sift4G

Pathogenic

0.0

.;D;D;.;.;.;.;.;.;.;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;D;.;.;.;D;.

Vest4

0.80, 0.84

MutPred

0.65

Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);Loss of glycosylation at S257 (P = 0.0217);

MVP

0.89

MPC

2.1

ClinPred

1.0

GERP RS

3.4

Varity_R

0.76

gMVP

0.90

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over