16-58019056-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_024598.4(USB1):c.693+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000178 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★).
Frequency
Consequence
NM_024598.4 splice_donor, intron
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 |
---|---|---|---|---|---|---|---|---|
USB1 | NM_024598.4 | c.693+1G>T | splice_donor_variant, intron_variant | Intron 6 of 6 | ENST00000219281.8 | NP_078874.2 | ||
USB1 | NM_001195302.2 | c.639+1G>T | splice_donor_variant, intron_variant | Intron 5 of 5 | NP_001182231.1 | |||
USB1 | NM_001330568.2 | c.540+1G>T | splice_donor_variant, intron_variant | Intron 6 of 6 | NP_001317497.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249902Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135152
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461808Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727210
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change affects a donor splice site in intron 6 of the USB1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with poikiloderma with neutropenia (PMID: 21271650). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 496749). 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 may disrupt the consensus splice site. This variant disrupts a region of the USB1 protein in which other variant(s) (p.Cys253Arg) have been observed in individuals with USB1-related conditions (PMID: 31522452). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Poikiloderma with neutropenia Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at