16-58001495-GC-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024598.4(USB1):c.16del(p.Leu6TrpfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,602,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
USB1
NM_024598.4 frameshift
NM_024598.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.222
Genes affected
USB1 (HGNC:25792): (U6 snRNA biogenesis phosphodiesterase 1) This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 16-58001495-GC-G is Pathogenic according to our data. Variant chr16-58001495-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1453838.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USB1 | NM_024598.4 | c.16del | p.Leu6TrpfsTer45 | frameshift_variant | 1/7 | ENST00000219281.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USB1 | ENST00000219281.8 | c.16del | p.Leu6TrpfsTer45 | frameshift_variant | 1/7 | 1 | NM_024598.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000310 AC: 7AN: 225922Hom.: 0 AF XY: 0.0000487 AC XY: 6AN XY: 123298
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GnomAD4 exome AF: 0.00000483 AC: 7AN: 1450486Hom.: 0 Cov.: 31 AF XY: 0.00000694 AC XY: 5AN XY: 720608
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74490
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 26, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with USB1-related conditions. This variant is present in population databases (rs781151070, gnomAD 0.04%). This sequence change creates a premature translational stop signal (p.Leu6Trpfs*45) in the USB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USB1 are known to be pathogenic (PMID: 20817924, 25044170). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at