rs387906799

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001244008.2(KIF1A):​c.296C>T​(p.Thr99Met) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

KIF1A
NM_001244008.2 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.74
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 2-240788118-G-A is Pathogenic according to our data. Variant chr2-240788118-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240788118-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1ANM_001244008.2 linkuse as main transcriptc.296C>T p.Thr99Met missense_variant 4/49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkuse as main transcriptc.296C>T p.Thr99Met missense_variant 4/495 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:5
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022The variant has been previously reported as de novo in a similarly affected individual (3billion dataset, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030169, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with NESCAV syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedresearchCHU Sainte-Justine Research Center, University of MontrealJan 01, 2014de novo mutation seen in 2 unrelated patients with a similar phenotype -
Pathogenic, criteria provided, single submitterresearchMolecular Medicine, University of PaviaJul 28, 2023- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 08, 2016- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 08, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 31, 2022Published functional studies demonstrate a damaging effect, impairing the ability of the protein to localize to distal aspects of neurites (Lee et al., 2015; Hamdan et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32737135, 26486474, 31785789, 21376300, 25253658, 25265257, 26125038, 32652677, 33753861, 33880452, 31069529, 21820098) -
KIF1A-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 05, 2024The KIF1A c.296C>T variant is predicted to result in the amino acid substitution p.Thr99Met. This variant has been reported as a recurrent de novo finding in individuals affected with autosomal dominant KIF1A related disorders (Hamdan et al. 2011. PubMed ID: 21376300; Okamoto et al. 2014. PubMed ID: 25253658; Langlois et al. 2016. PubMed ID: 26486474; Kaur et al. 2020. PubMed ID: 32652677; Nicita et al. 2020. PubMed ID: 32737135; Boyle et al. 2021. PubMed ID: 33880452; Paprocka et al. 2023. PubMed ID: 37239332). Functional studies have found this variant disrupts the ATP-binding site of the KIF1A motor domain, leading to a complete loss of motor function (Lee et al. 2015. PubMed ID: 25265257; Esmaeeli Nieh et al. 2015. PubMed ID: 26125038; Boyle et al. 2021. PubMed ID: 33880452). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
PEHO syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterliterature onlyChild and Family Research InstituteAug 06, 2015- -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 99 of the KIF1A protein (p.Thr99Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KIF1A-related conditions (PMID: 21376300, 25253658, 25265257, 26125038, 26486474). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30169). 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: 21376300, 25265257, 26125038). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.92
D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.7
H;H;.;.;.;.;.;H;.;.;.;H;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.1
.;D;D;.;.;.;.;.;.;.;.;D;.;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;D;.;.;.;.;.;.;.;.;D;.;.
Sift4G
Pathogenic
0.0
.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4
0.93, 0.92
MutPred
0.90
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.97
MPC
2.5
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.89
gMVP
0.96

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.

Other links and lift over

dbSNP: rs387906799; hg19: chr2-241727535; API