rs1554091442

Positions:

• chr5-179833623-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003900.5(SQSTM1):​c.1006G>A​(p.Asp336Asn) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3018946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1006G>A	p.Asp336Asn	missense_variant	7/8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.754G>A	p.Asp252Asn	missense_variant	8/9		NP_001135770.1
SQSTM1	NM_001142299.2	c.754G>A	p.Asp252Asn	missense_variant	8/9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1006G>A	p.Asp336Asn	missense_variant	7/8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.754G>A	p.Asp252Asn	missense_variant	6/7	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.950+396G>A		intron_variant		5		ENSP00000424477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

ClinVar contains an entry for this variant (Variation ID: 542160). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 336 of the SQSTM1 protein (p.Asp336Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.39	B;.
Vest4		0.29
MutPred		0.12		Loss of solvent accessibility (P = 0.0595);.;
MVP		0.97
MPC		0.19
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1554091442; hg19: chr5-179260623;