rs796051870
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PP3_StrongPP5_Moderate
The NM_003900.5(SQSTM1):c.1165+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
SQSTM1
NM_003900.5 splice_donor
NM_003900.5 splice_donor
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 9.26
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 14 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
?
BayesDel_addAF computational evidence supports a deleterious effect, 0.625
PP5
?
Variant 5-179833783-G-A is Pathogenic according to our data. Variant chr5-179833783-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8110.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-179833783-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.1165+1G>A | splice_donor_variant | ENST00000389805.9 | |||
SQSTM1 | NM_001142298.2 | c.913+1G>A | splice_donor_variant | ||||
SQSTM1 | NM_001142299.2 | c.913+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.1165+1G>A | splice_donor_variant | 1 | NM_003900.5 | P1 | |||
SQSTM1 | ENST00000360718.5 | c.913+1G>A | splice_donor_variant | 1 | |||||
SQSTM1 | ENST00000510187.5 | c.950+556G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250934Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135720
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461788Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 727190
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Paget disease of bone 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2002 | - - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | This sequence change affects a donor splice site in intron 7 of the SQSTM1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SQSTM1 cause disease. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products leading to truncation of C-terminal protein domains (PMID: 26208961). ClinVar contains an entry for this variant (Variation ID: 8110). This variant is also known as A390X. Disruption of this splice site has been observed in individuals with autosomal dominant SQSTM1-related conditions (PMID: 12374763, 17129171, 23417734, 26208961). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs796051870, gnomAD 0.0009%). - |
Myopathy, distal, with rimmed vacuoles Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 15
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at