rs587778791
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001244008.2(KIF1A):c.2840delT(p.Leu947ArgfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000129 in 1,550,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001244008.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000136 AC: 19AN: 1398358Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8AN XY: 689698
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
Neuropathy, hereditary sensory, type 2C Pathogenic:2
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Variant summary: KIF1A c.2555+1023delT (NM_004321.7) is located in the intron 25 of the KIF1A gene. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 150700 control chromosomes (gnomAD and publication data). The KIF1A gene comprises 47 exons plus some alternatively spliced coding exons and has multiple different transcripts. In one of the alternative transcripts (NM_001244008.1) the variant is predicted to cause a frameshift change (c.2840delT, p.Leu947ArgfsX4). Riviere et al (2011) report c.2840delT, in the homozygous and compound heterozygous state, in 4 different families with multiple individuals affected with Hereditary Sensory And Autonomic Neuropathy Type IIC. They specify the variant is located in the alternatively spliced exon 25b and provide evidence that KIF1A exon-25b-containing isoform is strongly expressed in the nervous system. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1
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KIF1A-related disorder Pathogenic:1
The KIF1A c.2840delT variant is predicted to result in a frameshift and premature protein termination (p.Leu947Argfs*4). This variant may also be described as ENST00000320389.11 c.2555+1023del, and has been reported to be causative for autosomal recessive hereditary sensory and autonomic neuropathy type II in nine patients from four families (Rivière et al. 2011. PubMed ID: 21820098). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in KIF1A are expected to be pathogenic. This variant is interpreted as pathogenic. -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1
This sequence change falls in intron 24 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive hereditary sensory and autonomic neuropathy (PMID: 21820098). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2840delT (p.Leu947Argfs*4). ClinVar contains an entry for this variant (Variation ID: 65859). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at