5-179833231-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.75

Publications

9 publications found

Variant links:

COSMIC-nc: COSV52975051

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

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 ClinVar 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 link	c.954C>T	p.Ser318Ser	synonymous_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.702C>T	p.Ser234Ser	synonymous_variant	Exon 7 of 9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.702C>T	p.Ser234Ser	synonymous_variant	Exon 7 of 9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 link	c.954C>T	p.Ser318Ser	synonymous_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 link	c.702C>T	p.Ser234Ser	synonymous_variant	Exon 5 of 7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000466342.1 link	n.653C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2
SQSTM1	ENST00000510187.5 link	c.950+4C>T		splice_region_variant, intron_variant	Intron 6 of 6	5		ENSP00000424477.1	E7EMC7

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5453

AN:

152118

Hom.:

177

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0213

AC XY:

15207

AN XY:

712876

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1691

3383

5074

6766

8457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

904

1808

2712

3616

4520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0359

AC:

5461

AN:

152236

Hom.:

179

Cov.:

AF XY:

0.0337

AC XY:

2511

AN XY:

74434

show subpopulations

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:

AN:

5174

South Asian (SAS)

AF:

0.0137

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0174

AC:

185

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0211

AC:

1435

AN:

68020

Other (OTH)

AF:

0.0322

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

268

535

803

1070

1338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0277

Hom.:

Bravo

AF:

0.0388

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over