rs4797

Variant names:

• chr5-179833213-G-A
• rs4797
• NM_003900.5:c.936G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-179833213-G-A
• chr5-179833213-G-C
• chr5-179833213-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003900.5(SQSTM1):​c.936G>A​(p.Arg312Arg) 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
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 259191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.936G>A	p.Arg312Arg	synonymous_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.684G>A	p.Arg228Arg	synonymous_variant	Exon 7 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.684G>A	p.Arg228Arg	synonymous_variant	Exon 7 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.936G>A	p.Arg312Arg	synonymous_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.684G>A	p.Arg228Arg	synonymous_variant	Exon 5 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.936G>A	p.Arg312Arg	synonymous_variant	Exon 6 of 7	5		ENSP00000424477.1
SQSTM1	ENST00000466342.1	n.635G>A		non_coding_transcript_exon_variant	Exon 4 of 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

GnomAD2 exomes AF: 0.599 AC: 142587 AN: 237962 AF XY: 0.592

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 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

African (AFR) AF: 0.438 AC: 14609 AN: 33358

American (AMR) AF: 0.754 AC: 33000 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 15718 AN: 26048

East Asian (EAS) AF: 0.800 AC: 31587 AN: 39472

South Asian (SAS) AF: 0.613 AC: 52588 AN: 85808

European-Finnish (FIN) AF: 0.618 AC: 32100 AN: 51940

Middle Eastern (MID) AF: 0.572 AC: 3226 AN: 5640

European-Non Finnish (NFE) AF: 0.520 AC: 576703 AN: 1109070

Other (OTH) AF: 0.552 AC: 33166 AN: 60092

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

African (AFR) AF: 0.447 AC: 18541 AN: 41448

American (AMR) AF: 0.654 AC: 9987 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2120 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4130 AN: 5150

South Asian (SAS) AF: 0.631 AC: 3040 AN: 4816

European-Finnish (FIN) AF: 0.620 AC: 6546 AN: 10560

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.528 AC: 35860 AN: 67946

Other (OTH) AF: 0.535 AC: 1127 AN: 2108

Alfa AF: 0.543 Hom.: 11347

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

-

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

- -

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

Jul 03, 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	-0.88
CADD	Benign	0.37
DANN	Benign	0.75
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4797; hg19: chr5-179260213; COSMIC: COSV108092080; COSMIC: COSV108092080;