rs886039781
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000389805.9(SQSTM1):c.311_312del(p.Glu104ValfsTer48) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SQSTM1
ENST00000389805.9 frameshift
ENST00000389805.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.73
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 Pathogenic. Variant got 18 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 5-179823864-AAG-A is Pathogenic according to our data. Variant chr5-179823864-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 265781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.311_312del | p.Glu104ValfsTer48 | frameshift_variant | 3/8 | ENST00000389805.9 | NP_003891.1 | |
SQSTM1 | NM_001142298.2 | c.59_60del | p.Glu20ValfsTer48 | frameshift_variant | 4/9 | NP_001135770.1 | ||
SQSTM1 | NM_001142299.2 | c.59_60del | p.Glu20ValfsTer48 | frameshift_variant | 4/9 | NP_001135771.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.311_312del | p.Glu104ValfsTer48 | frameshift_variant | 3/8 | 1 | NM_003900.5 | ENSP00000374455 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459676Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726174
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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726174
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The homozygous p.Glu104ValfsTer48 variant in SQSTM1 was identified by our study in one individual with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. The p.Glu104ValfsTer48 variant in SQSTM1 has been previously reported in 3 siblings from one family with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (PMID: 27545679) and segregated with disease in this family, but has been identified in 0.000008% (1/125568) of chromosomes by TopMed Bravo (https://bravo.sph.umich.edu/, dbSNP ID: rs748170760). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These previously reported individuals (PMID: 27545679) and the individual identified by our study were homozygotes, which increases the likelihood that the p.Glu104ValfsTer48 variant in SQSTM1 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265781) and has been interpreted as pathogenic by OMIM. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 104 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SQSTM1 gene is an established disease mechanism in autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3, PP1 (Richards 2015). - |
Neurodegeneration with ataxia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PP1,PM3,PM2 - |
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