5-179833153-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003900.5(SQSTM1):c.876C>T(p.Asp292Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,613,700 control chromosomes in the GnomAD database, including 262,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30584 hom., cov: 33)

Exomes 𝑓: 0.56 ( 232252 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.38

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 5-179833153-C-T is Benign according to our data. Variant chr5-179833153-C-T is described in ClinVar as [Benign]. Clinvar id is 259189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833153-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.876C>T	p.Asp292Asp	synonymous_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.624C>T	p.Asp208Asp	synonymous_variant	Exon 7 of 9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.624C>T	p.Asp208Asp	synonymous_variant	Exon 7 of 9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 link	c.876C>T	p.Asp292Asp	synonymous_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 link	c.624C>T	p.Asp208Asp	synonymous_variant	Exon 5 of 7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000510187.5 link	c.876C>T	p.Asp292Asp	synonymous_variant	Exon 6 of 7	5		ENSP00000424477.1	E7EMC7
SQSTM1	ENST00000466342.1 link	n.575C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

95039

AN:

151954

Hom.:

30556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.729

Gnomad AMI

AF:

0.663

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.640

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.620

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.606

GnomAD3 exomes

AF:

0.628

AC:

157513

AN:

250744

Hom.:

51224

AF XY:

0.617

AC XY:

83673

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.732

Gnomad AMR exome

AF:

0.791

Gnomad ASJ exome

AF:

0.644

Gnomad EAS exome

AF:

0.848

Gnomad SAS exome

AF:

0.633

Gnomad FIN exome

AF:

0.618

Gnomad NFE exome

AF:

0.528

Gnomad OTH exome

AF:

0.608

GnomAD4 exome

AF:

0.558

AC:

814997

AN:

1461628

Hom.:

232252

Cov.:

AF XY:

0.559

AC XY:

406325

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.736

Gnomad4 AMR exome

AF:

0.778

Gnomad4 ASJ exome

AF:

0.635

Gnomad4 EAS exome

AF:

0.861

Gnomad4 SAS exome

AF:

0.630

Gnomad4 FIN exome

AF:

0.615

Gnomad4 NFE exome

AF:

0.521

Gnomad4 OTH exome

AF:

0.582

GnomAD4 genome

AF:

0.625

AC:

95120

AN:

152072

Hom.:

30584

Cov.:

AF XY:

0.632

AC XY:

46994

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.728

Gnomad4 AMR

AF:

0.695

Gnomad4 ASJ

AF:

0.640

Gnomad4 EAS

AF:

0.848

Gnomad4 SAS

AF:

0.651

Gnomad4 FIN

AF:

0.620

Gnomad4 NFE

AF:

0.529

Gnomad4 OTH

AF:

0.608

Alfa

AF:

0.554

Hom.:

30077

Bravo

AF:

0.636

Asia WGS

AF:

0.762

AC:

2651

AN:

3478

EpiCase

AF:

0.528

EpiControl

AF:

0.530

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Paget disease of bone 2, early-onset

Benign:3

Apr 22, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paget disease of bone 3

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Aug 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, distal, with rimmed vacuoles

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.27

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over