rs777667891
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024598.4(USB1):βc.489_492delβ(p.Asn163LysfsTer101) variant causes a frameshift change. The variant allele was found at a frequency of 0.000018 in 1,613,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 32)
Exomes π: 0.000016 ( 0 hom. )
Consequence
USB1
NM_024598.4 frameshift
NM_024598.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.97
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]
Genome browser will be placed here
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 16-58014308-CCAAT-C is Pathogenic according to our data. Variant chr16-58014308-CCAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 496761.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-58014308-CCAAT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USB1 | NM_024598.4 | c.489_492del | p.Asn163LysfsTer101 | frameshift_variant | 4/7 | ENST00000219281.8 | |
USB1 | NM_001330568.2 | c.336_339del | p.Asn112LysfsTer101 | frameshift_variant | 4/7 | ||
USB1 | NM_001195302.2 | c.450-3022_450-3019del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USB1 | ENST00000219281.8 | c.489_492del | p.Asn163LysfsTer101 | frameshift_variant | 4/7 | 1 | NM_024598.4 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152066Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
5
AN:
152066
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251276Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135836
GnomAD3 exomes
AF:
AC:
3
AN:
251276
Hom.:
AF XY:
AC XY:
0
AN XY:
135836
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461530Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727084
GnomAD4 exome
AF:
AC:
24
AN:
1461530
Hom.:
AF XY:
AC XY:
8
AN XY:
727084
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74284
GnomAD4 genome
AF:
AC:
5
AN:
152066
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74284
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Poikiloderma with neutropenia Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 20, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | This variant is present in population databases (rs777667891, gnomAD 0.004%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the USB1 protein in which other variant(s) (p.Thr167Profs*98) have been determined to be pathogenic (PMID: 21271650). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 496761). This premature translational stop signal 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. This sequence change creates a premature translational stop signal (p.Asn163Lysfs*101) in the USB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acid(s) of the USB1 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 18
Find out detailed SpliceAI scores and Pangolin per-transcript scores at