3-183650357-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001349428.1(KLHL24):c.-966A>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001349428.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLHL24 | NM_017644.3 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 3 of 8 | ENST00000242810.11 | NP_060114.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The c.1 A>T variant in the KLHL24 gene has not been reported previously, however a different base pair substitution involving the initiation codon (c.1 A>G) is a common variant associated with generalized epidermolysis bullosa simplex (Lin et al., 2016; He et al., 2016). The c.1 A>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1 A>T variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1? using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. However, it has been shown that a downstream in frame Met initiation codon is used to initiate translation of a protein truncated by deletion of the initial 28 amino acids of the KLHL24 (KLHL24delta28) protein product in some patients (Lin et al., 2016; He et al., 2016). This protein was more stable than the normal protein and lead to increased ubiquitination and turnover of keratin 14. The pathobiology of Met1? in KLHL24 was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, the mutant was found to be associated with intermediate filament abnormalities in keratinocytes and fibroblasts (He et al., 2016). Therefore, KLHL24 pathogenic variants were described as a cause of skin fragility through regulation of turnover of keratin 14 and demonstrate that the KLHL24 protein plays a role in maintaining the balance between intermediate filament stability and degradation required for skin integrity. We interpret the c.1 A>T variant as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at