rs374244985
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_001244008.2(KIF1A):c.3680C>T(p.Pro1227Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,593,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1227Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001244008.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.3680C>T | p.Pro1227Leu | missense_variant | 35/49 | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.3680C>T | p.Pro1227Leu | missense_variant | 35/49 | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000211 AC: 46AN: 218374Hom.: 0 AF XY: 0.000210 AC XY: 25AN XY: 119068
GnomAD4 exome AF: 0.000121 AC: 175AN: 1441292Hom.: 1 Cov.: 31 AF XY: 0.000136 AC XY: 97AN XY: 715806
GnomAD4 genome AF: 0.000138 AC: 21AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74470
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 25, 2019 | The KIF1A c.3377C>T; p.Pro1126Leu variant (rs374244985), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 447653). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.1 percent in the Ashkenazi Jewish population (identified on 49 out of 249,768 chromosomes). The proline at position 1126 is weakly conserved and computational analyses of the effects of the p.Pro1126Leu variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Overall, there is not enough evidence to classify the p.Pro1126Leu variant with certainty. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2020 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2020 | The p.P1227L variant (also known as c.3680C>T), located in coding exon 34 of the KIF1A gene, results from a C to T substitution at nucleotide position 3680. The proline at codon 1227 is replaced by leucine, an amino acid with similar properties. This amino acid position is not 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. - |
Hereditary spastic paraplegia 30 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at