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GeneBe

5-179836470-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_003900.5(SQSTM1):c.1200G>C(p.Gln400His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q400K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SQSTM1
NM_003900.5 missense

Scores

1
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43
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 3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_003900.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_addAF=-0.00714517).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SQSTM1NM_003900.5 linkuse as main transcriptc.1200G>C p.Gln400His missense_variant 8/8 ENST00000389805.9
SQSTM1NM_001142298.2 linkuse as main transcriptc.948G>C p.Gln316His missense_variant 9/9
SQSTM1NM_001142299.2 linkuse as main transcriptc.948G>C p.Gln316His missense_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SQSTM1ENST00000389805.9 linkuse as main transcriptc.1200G>C p.Gln400His missense_variant 8/81 NM_003900.5 P1Q13501-1
SQSTM1ENST00000360718.5 linkuse as main transcriptc.948G>C p.Gln316His missense_variant 7/71 Q13501-2
MRNIPENST00000522663.5 linkuse as main transcriptc.*1220C>G 3_prime_UTR_variant, NMD_transcript_variant 9/91
SQSTM1ENST00000510187.5 linkuse as main transcriptc.951-1G>C splice_acceptor_variant 5

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

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 22, 2022In 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant has not been reported in the literature in individuals affected with SQSTM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 400 of the SQSTM1 protein (p.Gln400His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
-0.0071
T
BayesDel_noAF
Uncertain
-0.040
Cadd
Uncertain
23
Dann
Uncertain
0.99
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Benign
0.059
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
ClinPred
0.95
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chr5-179263470; API