rs11548633

chr5-179825184-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.06

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]

ACMG classification

Verdict is Benign. Variant got -16 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].
• BS2: High AC in GnomAd at 367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.712A>G	p.Lys238Glu	missense_variant	5/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.460A>G	p.Lys154Glu	missense_variant	6/9
SQSTM1	NM_001142299.2	c.460A>G	p.Lys154Glu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.712A>G	p.Lys238Glu	missense_variant	5/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152196 Hom.: 2 Cov.: 32

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.: 8 AF XY: 0.00322 AC XY: 437 AN XY: 135898

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.: 24 Cov.: 31 AF XY: 0.00357 AC XY: 2599 AN XY: 727138

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.: 2 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74500

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.: 1

Bravo AF: 0.00270

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	This variant is associated with the following publications: (PMID: 32594029, 29524522, 32409511, 32317127, 32028661, 31859009, 31445297, 28430856, 22972638, 24899140) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SQSTM1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	May 11, 2020	- -

Paget disease of bone 3 Benign:1

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

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Uncertain	-0.040	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
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	T
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

Other links and lift over

dbSNP: rs11548633; hg19: chr5-179252184; COSMIC: COSV62434480; COSMIC: COSV62434480;