rs1553638086

Positions:

• chr2-240783764-G-A
• chr2-240783764-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_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. 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. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.69

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 id is 1507070.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KIF1A
• 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 [Likely_pathogenic]. Clinvar id is 464261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240783764-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.773C>T	p.Thr258Met	missense_variant	8/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.773C>T	p.Thr258Met	missense_variant	8/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1431030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708762

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 15, 2020	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). -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33880452, 27535533, 32045731, 32935419, 30612907, 31488895, 28970574) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2018

- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 02, 2021

- -

Neuropathy, hereditary sensory, type 2C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 11, 2021

- -

Intellectual disability, autosomal dominant 9 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Sep 16, 2021

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

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; Invitae). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.;.;.;H;.;.;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	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	D
GERP RS		3.4
Varity_R		0.76
gMVP		0.90

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

Other links and lift over

dbSNP: rs1553638086; hg19: chr2-241723181; COSMIC: COSV57488905;