5-179836441-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003900.5(SQSTM1):​c.1171G>A​(p.Asp391Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SQSTM1
NM_003900.5 missense

Scores

2
14
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96
Variant links:
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]
MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SQSTM1NM_003900.5 linkc.1171G>A p.Asp391Asn missense_variant Exon 8 of 8 ENST00000389805.9 NP_003891.1 Q13501-1
SQSTM1NM_001142298.2 linkc.919G>A p.Asp307Asn missense_variant Exon 9 of 9 NP_001135770.1 Q13501-2
SQSTM1NM_001142299.2 linkc.919G>A p.Asp307Asn missense_variant Exon 9 of 9 NP_001135771.1 Q13501-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SQSTM1ENST00000389805.9 linkc.1171G>A p.Asp391Asn missense_variant Exon 8 of 8 1 NM_003900.5 ENSP00000374455.4 Q13501-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Uncertain:1
Jul 17, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 391 of the SQSTM1 protein (p.Asp391Asn). This variant is not present in population databases (gnomAD no frequency). 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: 1408637). 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. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Benign
1.9
L;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.93
P;.
Vest4
0.70
MutPred
0.32
Gain of helix (P = 0.062);.;
MVP
0.98
MPC
0.49
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.63
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179263441; API