5-179836442-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_003900.5(SQSTM1):ā€‹c.1172A>Gā€‹(p.Asp391Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,880 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 Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000068 ( 0 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.29
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.822
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SQSTM1NM_003900.5 linkc.1172A>G p.Asp391Gly missense_variant Exon 8 of 8 ENST00000389805.9 NP_003891.1 Q13501-1
SQSTM1NM_001142298.2 linkc.920A>G p.Asp307Gly missense_variant Exon 9 of 9 NP_001135770.1 Q13501-2
SQSTM1NM_001142299.2 linkc.920A>G p.Asp307Gly 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.1172A>G p.Asp391Gly missense_variant Exon 8 of 8 1 NM_003900.5 ENSP00000374455.4 Q13501-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251038
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Uncertain:1
Dec 22, 2024
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 glycine, which is neutral and non-polar, at codon 391 of the SQSTM1 protein (p.Asp391Gly). This variant is present in population databases (rs758452325, gnomAD 0.01%). 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: 2682914). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SQSTM1 protein function with a positive 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. -

not provided Uncertain:1
Feb 22, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;.
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.3
D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;.
Vest4
0.81
MutPred
0.36
Gain of helix (P = 0.062);.;
MVP
0.99
MPC
0.67
ClinPred
0.89
D
GERP RS
4.8
Varity_R
0.88
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs758452325; hg19: chr5-179263442; API