rs11548633

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003900.5(SQSTM1):c.712A>G(p.Lys238Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0034 in 1,614,012 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 24 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.06

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01183033).

BP6

Variant 5-179825184-A-G is Benign according to our data. Variant chr5-179825184-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 475403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179825184-A-G is described in Lovd as [Likely_benign]. Variant chr5-179825184-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00241 (367/152314) while in subpopulation SAS AF= 0.00394 (19/4828). AF 95% confidence interval is 0.00309. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.712A>G	p.Lys238Glu	missense_variant	Exon 5 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.460A>G	p.Lys154Glu	missense_variant	Exon 6 of 9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.460A>G	p.Lys154Glu	missense_variant	Exon 6 of 9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 link	c.712A>G	p.Lys238Glu	missense_variant	Exon 5 of 8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00282

AC:

708

AN:

251416

Hom.:

AF XY:

0.00322

AC XY:

437

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00351

AC:

5126

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

2599

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00492

Gnomad4 FIN exome

AF:

0.000544

Gnomad4 NFE exome

AF:

0.00390

Gnomad4 OTH exome

AF:

0.00293

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152314

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00346

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00333

Hom.:

Bravo

AF:

0.00270

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00241

AC:

293

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SQSTM1: BS2 -

Feb 09, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32594029, 29524522, 32409511, 32317127, 32028661, 31859009, 31445297, 28430856, 22972638, 24899140) -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 11, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paget disease of bone 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;D;T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

-0.040

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

D;D;T;D

Sift4G

Uncertain

0.010

D;T;D;T

Polyphen

0.72, 0.91

.;P;P;.

Vest4

0.67, 0.69, 0.70

MVP

0.94

MPC

0.45

ClinPred

0.018

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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