5-179821034-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003900.5(SQSTM1):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,554,964 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A33T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: 2.76

Publications

14 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:

ENSG00000301422 (HGNC:):

ENSG00000301422 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010404259).

BP6

Variant 5-179821034-C-T is Benign according to our data. Variant chr5-179821034-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253029.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000735 (112/152306) while in subpopulation NFE AF = 0.00126 (86/68006). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.-47-1924C>T		intron_variant	Intron 2 of 8		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.-47-1924C>T		intron_variant	Intron 2 of 8		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000813

AC:

137

AN:

168614

AF XY:

0.000845

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.000850

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000709

GnomAD4 exome

AF:

0.00115

AC:

1617

AN:

1402658

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

791

AN XY:

696570

show subpopulations

African (AFR)

AF:

0.000205

AC:

AN:

29210

American (AMR)

AF:

0.000772

AC:

AN:

40158

Ashkenazi Jewish (ASJ)

AF:

0.0000808

AC:

AN:

24740

East Asian (EAS)

AF:

0.00

AC:

AN:

34584

South Asian (SAS)

AF:

0.000247

AC:

AN:

80932

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

37154

Middle Eastern (MID)

AF:

0.00166

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.00131

AC:

1431

AN:

1092168

Other (OTH)

AF:

0.00106

AC:

AN:

58286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

199

298

398

497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.000735

AC:

112

AN:

152306

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41580

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00118

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000812

AC:

ExAC

AF:

0.000679

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

Pathogenic:1

Nov 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Sep 27, 2023

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.98C>T (p.Ala33Val) results in a non-conservative amino acid change located in the PB1 domain (IPR000270) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 168614 control chromosomes (gnomAD). c.98C>T has been reported in the literature in individuals affected with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, some of whom had a positive family history of similar disorders, but with no segregation data available (e.g. Fecto_2011, Le Ber_2013, van der Zee_2014, Borghero_2016, Goldstein_2019, McCann_2020, Mol_2021). Additionally, the variant has also been reported in controls (e.g. van der Zee_2014, Mol_2021) and in at least one case, the affected individual also harbored a potentially pathogenic variant in a different gene (e.g. Borghero_2016). Therefore, 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: 27156075, 22084127, 31108397, 24042580, 32409511, 32843152, 24899140). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Oct 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Unlikely to be causative of SQSTM1-related frontotemporal dementia/amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31108397, 26836416, 24138988, 24486447, 25796131, 25382069, 23447461, 27275741, 27156075, 22084127, 24042580, 24899140) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T;T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.74

T;.;D;.

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.69

N;.;.;.

PhyloP100

2.8

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.040

N;.;N;N

REVEL

Benign

0.049

Sift

Benign

0.42

T;.;T;T

Sift4G

Benign

0.54

T;D;T;T

Polyphen

0.0080

B;.;.;B

Vest4

0.30

MVP

0.88

MPC

0.13

ClinPred

0.028

GERP RS

0.80

PromoterAI

-0.0083

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.078

gMVP

0.35

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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