rs759761915
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024598.4(USB1):c.176_177del(p.Gly59AlafsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
USB1
NM_024598.4 frameshift
NM_024598.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.36
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-58002553-AGG-A is Pathogenic according to our data. Variant chr16-58002553-AGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 496750.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-58002553-AGG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USB1 | NM_024598.4 | c.176_177del | p.Gly59AlafsTer2 | frameshift_variant | 2/7 | ENST00000219281.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USB1 | ENST00000219281.8 | c.176_177del | p.Gly59AlafsTer2 | frameshift_variant | 2/7 | 1 | NM_024598.4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251290Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461818Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727200
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 02, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496750). This premature translational stop signal has been observed in individual(s) with Rothmund–Thomson syndrome (PMID: 20817924). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly59Alafs*2) 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). - |
Poikiloderma with neutropenia Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
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