rs145056421

chr5-179824013-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003900.5(SQSTM1):c.457G>A(p.Val153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.41

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30709404).
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.457G>A	p.Val153Ile	missense_variant	3/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.205G>A	p.Val69Ile	missense_variant	4/9
SQSTM1	NM_001142299.2	c.205G>A	p.Val69Ile	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.457G>A	p.Val153Ile	missense_variant	3/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 251200 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.000370 AC XY: 269 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2022	Reported in individuals with ALS and in unaffected controls (Fecto et al., 2011; Shimizu et al., 2013; van der Zee et al., 2014; Cady et al., 2015; Cuyvers et al., 2015; Morgan et al., 2017; Yilmaz et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26234378, 35240373, 28166811, 25796131, 32594029, 31859009, 34009082, 23812289, 24899140, 22084127, 27275741, 28430856, 25382069) -

Paget disease of bone 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Jan 15, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 153 of the SQSTM1 protein (p.Val153Ile). This variant is present in population databases (rs145056421, gnomAD 0.04%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 22084127, 23812289, 24899140, 25796131, 31859009). ClinVar contains an entry for this variant (Variation ID: 571746). 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 with a negative 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. -

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

This sequence change in SQSTM1 is predicted to replace valine with isoleucine at codon 153, p.(Val153Ile). The valine residue is weakly conserved (100 vertebrates, UCSC), and is located in the zinc finger domain. There is a small physicochemical difference between valine and isoleucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.042% (54/128,964 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with amyotrophic lateral sclerosis (PMID: 22084127, 23812289). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.161). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4 -

SQSTM1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

The SQSTM1 c.457G>A variant is predicted to result in the amino acid substitution p.Val153Ile. This variant was reported in an individual with amyotrophic lateral sclerosis (ALS) who also carried an additional missense variant in SQSTM1 in trans (Shimizu et al. 2013. PubMed ID: 23812289) and has been observed in other patients with ALS (Table 1 in Yilmaz et al. 2019. PubMed ID: 31859009; Fecto et al. 2011. PubMed ID: 22084127). In another study, this variant was found in one patient with ALS, but also observed in three controls (Table 2, van der Zee et al. 2014. PubMed ID: 24899140). In a large ALS case-control study, the c.457G>A variant was reported in one healthy control but not in any individuals with ALS (Morgan et al. 2017. PubMed ID: 28430856). This variant has also been observed in an individual with glaucoma and and individual with Alzheimer disease, but was also observed in otherwise healthy controls in both studies (Scheetz et al. 2016. PubMed ID: 27275741; Table 1 Cuyvers et al. 2015. PubMed ID: 25796131). This variant is reported in 0.042% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common for a fully penetrant autosomal dominant variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.93	D;D;D;D;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.077	T;T;T;T;T;T
Sift4G	Benign	0.081	T;T;T;T;T;T
Polyphen		0.011, 0.56	.;.;B;.;P;.
Vest4		0.44, 0.73, 0.40
MVP		0.82
MPC		0.11
ClinPred		0.015	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.32
gMVP		0.34

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: rs145056421; hg19: chr5-179251013;