rs4797

chr5-179833213-G-Achr5-179833213-G-Cchr5-179833213-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003900.5(SQSTM1):c.936G>A(p.Arg312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,607,140 control chromosomes in the GnomAD database, including 242,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R312R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.54 (22769 hom., cov: 32)
  • Exomes 𝑓: 0.54 (219492 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-179833213-G-A is Benign according to our data. Variant chr5-179833213-G-A is described in ClinVar as [Benign]. Clinvar id is 259191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833213-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.936G>A	p.Arg312=	synonymous_variant	6/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.684G>A	p.Arg228=	synonymous_variant	7/9
SQSTM1	NM_001142299.2	c.684G>A	p.Arg228=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.936G>A	p.Arg312=	synonymous_variant	6/8	1	NM_003900.5	P1
SQSTM1	ENST00000360718.5	c.684G>A	p.Arg228=	synonymous_variant	5/7	1
SQSTM1	ENST00000510187.5	c.936G>A	p.Arg312=	synonymous_variant	6/7	5
SQSTM1	ENST00000466342.1	n.635G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82031 AN: 151854 Hom.: 22752 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.531

GnomAD3 exomes AF: 0.599 AC: 142587 AN: 237962 Hom.: 44118 AF XY: 0.592 AC XY: 76557 AN XY: 129232

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.770

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.814

Gnomad SAS exome AF: 0.616

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.545 AC: 792697 AN: 1455168 Hom.: 219492 Cov.: 65 AF XY: 0.547 AC XY: 395502 AN XY: 723464

Gnomad4 AFR exome AF: 0.438

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.800

Gnomad4 SAS exome AF: 0.613

Gnomad4 FIN exome AF: 0.618

Gnomad4 NFE exome AF: 0.520

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.540 AC: 82084 AN: 151972 Hom.: 22769 Cov.: 32 AF XY: 0.550 AC XY: 40862 AN XY: 74242

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.654

Gnomad4 ASJ AF: 0.611

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.528

Gnomad4 OTH AF: 0.535

Alfa AF: 0.538 Hom.: 8477

Bravo AF: 0.538

Asia WGS AF: 0.708 AC: 2463 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Paget disease of bone 2, early-onset Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Paget disease of bone 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -

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

Feb 01, 2024

- -

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Myopathy, distal, with rimmed vacuoles Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.37
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4797; hg19: chr5-179260213;