rs672601364
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_001244008.2(KIF1A):c.430G>T(p.Val144Phe) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 34)
Consequence
KIF1A
NM_001244008.2 missense, splice_region
NM_001244008.2 missense, splice_region
Scores
11
6
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 7.71
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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, 0.938
PP5
Variant 2-240786513-C-A is Pathogenic according to our data. Variant chr2-240786513-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162054.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.430G>T | p.Val144Phe | missense_variant, splice_region_variant | 6/49 | ENST00000498729.9 | NP_001230937.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.430G>T | p.Val144Phe | missense_variant, splice_region_variant | 6/49 | 5 | NM_001244008.2 | ENSP00000438388 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 9 Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | CHU Sainte-Justine Research Center, University of Montreal | Jan 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jun 15, 2020 | This variant is interpreted as likely pathogenic for NESCAV syndrome, 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.;.;.;.;L;.;.;.;L;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G
Pathogenic
.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen
D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4
0.93, 0.95
MutPred
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.92
MPC
2.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at