rs55793208

Variant names:

• chr5-179833099-G-C
• rs55793208
• NM_003900.5:c.822G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003900.5(SQSTM1):​c.822G>C​(p.Glu274Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,204 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 33)
  • Exomes 𝑓: 0.020 (369 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.240
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022973716).
• BP6: Variant 5-179833099-G-C is Benign according to our data. Variant chr5-179833099-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2343/152324) while in subpopulation NFE AF = 0.0212 (1445/68034). AF 95% confidence interval is 0.0203. There are 32 homozygotes in GnomAd4. There are 1068 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.822G>C	p.Glu274Asp	missense_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.570G>C	p.Glu190Asp	missense_variant	Exon 7 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.570G>C	p.Glu190Asp	missense_variant	Exon 7 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.822G>C	p.Glu274Asp	missense_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.570G>C	p.Glu190Asp	missense_variant	Exon 5 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.822G>C	p.Glu274Asp	missense_variant	Exon 6 of 7	5		ENSP00000424477.1
SQSTM1	ENST00000466342.1	n.521G>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 152206 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0178 AC: 4480 AN: 251422 AF XY: 0.0189

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.00893

Gnomad ASJ exome AF: 0.0495

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0201 AC: 29429 AN: 1461880 Hom.: 369 Cov.: 46 AF XY: 0.0202 AC XY: 14725 AN XY: 727240

African (AFR) AF: 0.00376 AC: 126 AN: 33480

American (AMR) AF: 0.00932 AC: 417 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0509 AC: 1330 AN: 26132

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0168 AC: 1446 AN: 86258

European-Finnish (FIN) AF: 0.0180 AC: 959 AN: 53418

Middle Eastern (MID) AF: 0.0362 AC: 209 AN: 5768

European-Non Finnish (NFE) AF: 0.0212 AC: 23590 AN: 1112004

Other (OTH) AF: 0.0222 AC: 1338 AN: 60396

GnomAD4 genome AF: 0.0154 AC: 2343 AN: 152324 Hom.: 32 Cov.: 33 AF XY: 0.0143 AC XY: 1068 AN XY: 74482

African (AFR) AF: 0.00356 AC: 148 AN: 41572

American (AMR) AF: 0.0155 AC: 237 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4832

European-Finnish (FIN) AF: 0.0176 AC: 187 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1445 AN: 68034

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0225 Hom.: 18

Bravo AF: 0.0152

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0177 AC: 2153

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0235

EpiControl AF: 0.0248

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 19, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22972638, 25617006, 27275741, 24899140, 23942205, 25681989, 25796131, 15164150, 24042580) -

Paget disease of bone 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paget disease of bone 2, early-onset Benign:1

Nov 24, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.0
DANN	Benign	0.69
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.61	T;.;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		-0.24
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.057
MutPred		0.028		Loss of glycosylation at S276 (P = 0.1499);Loss of glycosylation at S276 (P = 0.1499);.;
MPC		0.12
ClinPred		0.0018	T
GERP RS		-6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.13
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55793208; hg19: chr5-179260099; COSMIC: COSV52975046;