5-179833585-AG-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePP3_ModerateBS2_Supporting
The NM_003900.5(SQSTM1):c.970del variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000062 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
SQSTM1
NM_003900.5 splice_acceptor
NM_003900.5 splice_acceptor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.97
Genes affected
SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]
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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 0.073696144 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 0 (no position change), new splice context is: catggtgagttttgttccAGaac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.970del | splice_acceptor_variant | ENST00000389805.9 | |||
SQSTM1 | NM_001142298.2 | c.718del | splice_acceptor_variant | ||||
SQSTM1 | NM_001142299.2 | c.718del | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.970del | splice_acceptor_variant | 1 | NM_003900.5 | P1 | |||
SQSTM1 | ENST00000360718.5 | c.718del | splice_acceptor_variant | 1 | |||||
SQSTM1 | ENST00000510187.5 | c.950+360del | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251330Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461852Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727228
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74468
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 18, 2022 | This sequence change creates a premature translational stop signal (p.Glu324Asnfs*54) in the SQSTM1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 117 amino acid(s) of the SQSTM1 protein. This variant is present in population databases (rs758377403, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SQSTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542159). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2020 | - - |
Myopathy, distal, with rimmed vacuoles Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The splice acceptor c.970del variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.970del variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in gnomAD database. This variant has been reported to the ClinVar database as Uncertain Significance. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Uncertain Significance. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 3
DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at