rs772449700
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_001244008.2(KIF1A):c.4665+4G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,545,912 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 1 hom. )
Consequence
KIF1A
NM_001244008.2 splice_donor_region, intron
NM_001244008.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001787
2
Clinical Significance
Conservation
PhyloP100: 0.421
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 Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000366 (51/1393772) while in subpopulation SAS AF= 0.000543 (43/79130). AF 95% confidence interval is 0.000414. There are 1 homozygotes in gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF1A | NM_001244008.2 | c.4665+4G>C | splice_donor_region_variant, intron_variant | ENST00000498729.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF1A | ENST00000498729.9 | c.4665+4G>C | splice_donor_region_variant, intron_variant | 5 | NM_001244008.2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000748 AC: 11AN: 147070Hom.: 0 AF XY: 0.0000886 AC XY: 7AN XY: 79030
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GnomAD4 exome AF: 0.0000366 AC: 51AN: 1393772Hom.: 1 Cov.: 32 AF XY: 0.0000524 AC XY: 36AN XY: 687532
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 29, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2022 | The c.4362+4G>C intronic alteration consists of a G to C substitution nucleotides after coding exon 40 in the KIF1A gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Intellectual disability, autosomal dominant 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice site c.4665+4G>C variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has allele frequency 0.007% in gnomAD exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The c.4362+4G>C variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. The c.4665+4G>C variant is not predicted to disrupt splicing by any splice site algorithm. For these reasons, this variant has been classified as Uncertain Significance (VUS). - |
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 | Invitae | Aug 31, 2023 | This sequence change falls in intron 40 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. It affects a nucleotide within the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 435623). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. This variant is present in population databases (rs772449700, gnomAD 0.05%). - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at