rs145056421

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

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. 16/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 1.41

Publications

11 publications found

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]

SQSTM1 Gene-Disease associations (from GenCC):

neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
osteosarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Paget disease of bone 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
behavioral variant of frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30709404).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000276 (42/152220) while in subpopulation NFE AF = 0.000485 (33/68042). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SQSTM1	NM_003900.5 link	c.457G>A	p.Val153Ile	missense_variant	Exon 3 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2 link	c.205G>A	p.Val69Ile	missense_variant	Exon 4 of 9		NP_001135770.1
SQSTM1	NM_001142299.2 link	c.205G>A	p.Val69Ile	missense_variant	Exon 4 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 link	c.457G>A	p.Val153Ile	missense_variant	Exon 3 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000291

AC:

AN:

251200

AF XY:

0.000294

show subpopulations

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 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.:

Cov.:

AF XY:

0.000370

AC XY:

269

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000398

AC:

443

AN:

1112012

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000276

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68042

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000513

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jul 13, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Feb 28, 2023

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 13, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

not specified

Uncertain:1

Jun 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SQSTM1 c.457G>A (p.Val153Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251200 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SQSTM1 causing SQSTM1-Related Disorders, allowing no conclusion about variant significance. c.457G>A has been reported in the literature in individuals affected with Amyotrophic lateral sclerosis as well as unaffected controls (e.g. Fecto_2011, Shimizu_2013, van der Zee_2014, Yilmaz_2020). These reports do not provide unequivocal conclusions about association of the variant with SQSTM1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22084127, 23812289, 24899140, 31859009). ClinVar contains an entry for this variant (Variation ID: 571746). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Paget disease of bone 3

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

Uncertain:1

Jun 06, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SQSTM1 c.457G>A variant is predicted to result in the amino acid substitution p.Val153Ile. This variant has been 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, 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 an 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. -

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). 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 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. -

Paget disease of bone 3;C4225326:Frontotemporal dementia and/or amyotrophic lateral sclerosis 3;C4310693:Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset;C5399975:Myopathy, distal, with rimmed vacuoles

Uncertain:1

Dec 02, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.28

.;.;T;T;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.93

D;D;D;D;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.31

T;T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.64

.;.;N;.;.;.

PhyloP100

1.4

PrimateAI

Benign

0.29

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

GERP RS

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.32

gMVP

0.34

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over