5-179820937-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PS1_ModeratePP5
The NM_003900.5(SQSTM1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,547,986 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
SQSTM1
NM_003900.5 start_lost
NM_003900.5 start_lost
Scores
6
2
8
Clinical Significance
Conservation
PhyloP100: 3.16
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 11 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_003900.5 (SQSTM1) was described as [Pathogenic] in ClinVar as 265780
PP5
?
Variant 5-179820937-A-G is Pathogenic according to our data. Variant chr5-179820937-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019776.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SQSTM1 | NM_003900.5 | c.1A>G | p.Met1? | start_lost | 1/8 | ENST00000389805.9 | |
SQSTM1 | NM_001142298.2 | c.-47-2021A>G | intron_variant | ||||
SQSTM1 | NM_001142299.2 | c.-47-2021A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SQSTM1 | ENST00000389805.9 | c.1A>G | p.Met1? | start_lost | 1/8 | 1 | NM_003900.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152074Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 0.0000115 AC: 16AN: 1395912Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 9AN XY: 691524
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 24, 2020 | The SQSTM1 c.1A>G (p.Met1?) variant disrupts the initiation codon and is predicted to interfere with normal protein expression. A different nucleotide change that also disrupts the initiation codon, c.2T>A, has been reported in a homozygous state in three siblings with childhood-onset neurodegeneration with ataxia, dystonia, gaze palsy and cognitive decline. Analysis of fibroblasts from affected individuals in this family, indicated the absence of any translated gene product (Haack et al. 2016). The c.1A>G variant is reported at a frequency of 0.000230 in the African/African-American population of the Genome Aggregation Database, which is based on two alleles in a region of good sequencing coverage. One additional allele affecting the initiation codon is also present in the Ashkenazi Jewish population. Based on the collective evidence, the c.1A>G variant is classified as likely pathogenic for childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2023 | Disruption of the initiator codon has been observed in individual(s) with autosomal recessive neurodegeneration with ataxia, dystonia, and gaze palsy (PMID: 27545679). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1019776). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the SQSTM1 mRNA. The next in-frame methionine is located at codon 85. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 13, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;.;N;N
REVEL
Benign
Sift
Pathogenic
D;.;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
P;.;.;B
Vest4
MutPred
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at