rs200152247
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_003900.5(SQSTM1):c.352C>T(p.Pro118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
SQSTM1
NM_003900.5 missense
NM_003900.5 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 3.71
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.29185352).
BS2
High AC in GnomAd4 at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.352C>T | p.Pro118Ser | missense_variant | 3/8 | ENST00000389805.9 | |
SQSTM1 | NM_001142298.2 | c.100C>T | p.Pro34Ser | missense_variant | 4/9 | ||
SQSTM1 | NM_001142299.2 | c.100C>T | p.Pro34Ser | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.352C>T | p.Pro118Ser | missense_variant | 3/8 | 1 | NM_003900.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000124 AC: 31AN: 250558Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135594
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GnomAD4 exome AF: 0.000210 AC: 307AN: 1461196Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 140AN XY: 726928
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24899140, 25796131, 32397312, 27275741) - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 12-16-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.352C>T (p.P118S) alteration is located in exon 3 (coding exon 3) of the SQSTM1 gene. This alteration results from a C to T substitution at nucleotide position 352, causing the proline (P) at amino acid position 118 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
SQSTM1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2023 | The SQSTM1 c.352C>T variant is predicted to result in the amino acid substitution p.Pro118Ser. This variant was reported in an individual(s) with amyotrophic lateral sclerosis (Scarlino et al 2020. PubMed ID: 32397312). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-179250908-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | Jan 19, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 118 of the SQSTM1 protein (p.Pro118Ser). This variant is present in population databases (rs200152247, gnomAD 0.02%). 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: 567262). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SQSTM1 protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;.;L;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;T;T;T
Sift4G
Uncertain
D;D;D;D;D;T
Polyphen
0.0090, 0.34
.;.;B;.;B;.
Vest4
0.29, 0.29
MVP
MPC
0.13
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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