chr5-179833231-C-T

Variant names:

• chr5-179833231-C-T
• rs56092424
• NM_003900.5:c.954C>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.954C>T​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,588,584 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (179 hom., cov: 33)
  • Exomes 𝑓: 0.022 (453 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.75
• Publications: 9 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=-0.76).
• BP6: Variant 5-179833231-C-T is Benign according to our data. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833231-C-T is described in CliVar as Benign. Clinvar id is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.954C>T	p.Ser318Ser	synonymous_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.702C>T	p.Ser234Ser	synonymous_variant	Exon 7 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.702C>T	p.Ser234Ser	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.954C>T	p.Ser318Ser	synonymous_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.702C>T	p.Ser234Ser	synonymous_variant	Exon 5 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000466342.1	n.653C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2
SQSTM1	ENST00000510187.5	c.950+4C>T		splice_region_variant, intron_variant	Intron 6 of 6	5		ENSP00000424477.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5453 AN: 152118 Hom.: 177 Cov.: 33

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0212 AC: 4300 AN: 202768 AF XY: 0.0205

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.000341

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0217 AC: 31140 AN: 1436348 Hom.: 453 Cov.: 36 AF XY: 0.0213 AC XY: 15207 AN XY: 712876

African (AFR) AF: 0.0749 AC: 2469 AN: 32948

American (AMR) AF: 0.0134 AC: 546 AN: 40726

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1288 AN: 25738

East Asian (EAS) AF: 0.000287 AC: 11 AN: 38288

South Asian (SAS) AF: 0.0140 AC: 1181 AN: 84096

European-Finnish (FIN) AF: 0.0171 AC: 822 AN: 47986

Middle Eastern (MID) AF: 0.0380 AC: 193 AN: 5084

European-Non Finnish (NFE) AF: 0.0209 AC: 23074 AN: 1102074

Other (OTH) AF: 0.0262 AC: 1556 AN: 59408

GnomAD4 genome AF: 0.0359 AC: 5461 AN: 152236 Hom.: 179 Cov.: 33 AF XY: 0.0337 AC XY: 2511 AN XY: 74434

African (AFR) AF: 0.0751 AC: 3120 AN: 41522

American (AMR) AF: 0.0241 AC: 369 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4824

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1435 AN: 68020

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0277 Hom.: 20

Bravo AF: 0.0388

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 19, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paget disease of bone 3 Benign:1

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paget disease of bone 2, early-onset Benign:1

Nov 24, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.18
DANN	Benign	0.88
PhyloP100		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs56092424; hg19: chr5-179260231; COSMIC: COSV52975051;