chr15-50496085-G-GTAAGT
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PVS1_ModeratePM2PP3BP6_Moderate
The NM_005154.5(USP8):c.2895+3_2895+7dup variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Consequence
USP8
NM_005154.5 splice_donor
NM_005154.5 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.58
Genes affected
USP8 (HGNC:12631): (ubiquitin specific peptidase 8) This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]
USP50 (HGNC:20079): (ubiquitin specific peptidase 50) Enables ubiquitin-like protein-specific protease activity. Acts upstream of or within several processes, including nuclear speck organization; positive regulation of NLRP3 inflammasome complex assembly; and positive regulation of macromolecule metabolic process. Predicted to be active in several cellular components, including dendritic spine; midbody; and postsynaptic density. Predicted to be extrinsic component of endosome membrane and extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.07030086 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: cagGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
BP6
?
Variant 15-50496085-G-GTAAGT is Benign according to our data. Variant chr15-50496085-G-GTAAGT is described in ClinVar as [Likely_benign]. Clinvar id is 706806.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USP8 | NM_005154.5 | c.2895+3_2895+7dup | splice_donor_variant | ENST00000307179.9 | |||
USP8 | NM_001128610.3 | c.2895+3_2895+7dup | splice_donor_variant | ||||
USP8 | NM_001283049.2 | c.2577+3_2577+7dup | splice_donor_variant | ||||
USP50 | XR_007064444.1 | n.1917+811_1917+812insACTTA | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USP8 | ENST00000307179.9 | c.2895+3_2895+7dup | splice_donor_variant | 1 | NM_005154.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245698Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132702
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GnomAD4 exome Cov.: 27
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2017 | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at