rs146164139

Positions:

chr5-179833601-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003900.5(SQSTM1):c.984G>A(p.Ser328Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,132 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 22 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.30

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 5-179833601-G-A is Benign according to our data. Variant chr5-179833601-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833601-G-A is described in Lovd as [Benign]. Variant chr5-179833601-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.3 with no splicing effect.

BS2

High AC in GnomAd4 at 571 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5 linkuse as main transcript	c.984G>A	p.Ser328Ser	synonymous_variant	7/8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.732G>A	p.Ser244Ser	synonymous_variant	8/9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 linkuse as main transcript	c.732G>A	p.Ser244Ser	synonymous_variant	8/9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.984G>A	p.Ser328Ser	synonymous_variant	7/8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.732G>A	p.Ser244Ser	synonymous_variant	6/7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+374G>A		intron_variant		5		ENSP00000424477.1	E7EMC7

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00498

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00446

AC:

1122

AN:

251388

Hom.:

AF XY:

0.00447

AC XY:

607

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00399

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00948

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.00411

AC:

6005

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3000

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00461

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.0106

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00459

GnomAD4 genome

AF:

0.00375

AC:

571

AN:

152258

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.00498

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00481

Hom.:

Bravo

AF:

0.00344

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	This variant is associated with the following publications: (PMID: 25796131) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SQSTM1: BP4, BP7, BS2 -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2021	- -

Paget disease of bone 3

Benign:1

Benign, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.0

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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