X-72330078-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_018486.3(HDAC8):c.1112-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_018486.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HDAC8 | ENST00000373573.9 | c.1112-2A>G | splice_acceptor_variant, intron_variant | Intron 10 of 10 | 1 | NM_018486.3 | ENSP00000362674.3 | |||
ENSG00000285547 | ENST00000648922.1 | c.1111+21655A>G | intron_variant | Intron 10 of 11 | ENSP00000497072.1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 5 Pathogenic:1Uncertain:1
This sequence change affects an acceptor splice site in the last intron (intron 10) of the HDAC8 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HDAC8-related disease. Nucleotide substitutions within 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at