NM_001244008.2:c.4909G>A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001244008.2(KIF1A):c.4909G>A(p.Glu1637Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,611,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000102 AC: 25AN: 245506Hom.: 0 AF XY: 0.000120 AC XY: 16AN XY: 133784
GnomAD4 exome AF: 0.0000617 AC: 90AN: 1459374Hom.: 0 Cov.: 30 AF XY: 0.0000675 AC XY: 49AN XY: 725954
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2
The KIF1A c.4606G>A; p.Glu1536Lys variant (rs377032453), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 532868). This variant is found in the general population with an overall allele frequency of 0.01% (26/276844 alleles) in the Genome Aggregation Database. The glutamate at codon 1536 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Glu1536Lys variant is uncertain at this time. -
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Inborn genetic diseases Uncertain:1
The p.E1637K variant (also known as c.4909G>A), located in coding exon 45 of the KIF1A gene, results from a G to A substitution at nucleotide position 4909. The glutamic acid at codon 1637 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Intellectual disability, autosomal dominant 9 Uncertain:1
The missense variant c.4909G>A (p.Glu1637Lys) in KIF1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu1637Lys variant has allele frequency 0.009% in gnomAD exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Glu at position 1637 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu1637Lys in KIF1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
Neuropathy, hereditary sensory, type 2C Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Hereditary spastic paraplegia 30 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Neuropathy, hereditary sensory and autonomic, type 2A;C3280168:Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Uncertain:1
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Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at