9-108874894-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_003640.5(ELP1):c.3931+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. 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_003640.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ELP1 | NM_003640.5 | c.3931+1G>A | splice_donor_variant, intron_variant | Intron 36 of 36 | ENST00000374647.10 | NP_003631.2 | ||
ELP1 | NM_001318360.2 | c.3589+1G>A | splice_donor_variant, intron_variant | Intron 36 of 36 | NP_001305289.1 | |||
ELP1 | NM_001330749.2 | c.2884+1G>A | splice_donor_variant, intron_variant | Intron 34 of 34 | NP_001317678.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial dysautonomia Uncertain:1
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not provided Uncertain:1
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. This sequence change affects a donor splice site in the last intron (intron 36) of the IKBKAP 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 IKBKAP-related disease. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at