chr5-179833231-C-T

Position:

chr5-179833231-C-T

Variant summary

Our verdict is Benign. Variant got -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

Variant links:

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 links:

SQSTM1 (HGNC:):

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr5-179833231-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5 linkuse as main transcript	c.954C>T	p.Ser318Ser	synonymous_variant	6/8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.702C>T	p.Ser234Ser	synonymous_variant	7/9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 linkuse as main transcript	c.702C>T	p.Ser234Ser	synonymous_variant	7/9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.954C>T	p.Ser318Ser	synonymous_variant	6/8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.702C>T	p.Ser234Ser	synonymous_variant	5/7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+4C>T		splice_region_variant, intron_variant		5		ENSP00000424477.1	E7EMC7
SQSTM1	ENST00000466342.1 linkuse as main transcript	n.653C>T		non_coding_transcript_exon_variant	4/4	2

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

GnomAD3 exomes

AF:

0.0212

AC:

4300

AN:

202768

Hom.:

AF XY:

0.0205

AC XY:

2271

AN XY:

110882

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 SAS exome

AF:

0.0144

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

Gnomad4 AFR exome

AF:

0.0749

Gnomad4 AMR exome

AF:

0.0134

Gnomad4 ASJ exome

AF:

0.0500

Gnomad4 EAS exome

AF:

0.000287

Gnomad4 SAS exome

AF:

0.0140

Gnomad4 FIN exome

AF:

0.0171

Gnomad4 NFE exome

AF:

0.0209

Gnomad4 OTH exome

AF:

0.0262

GnomAD4 genome

AF:

0.0359

AC:

5461

AN:

152236

Hom.:

179

Cov.:

AF XY:

0.0337

AC XY:

2511

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0751

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0432

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0322

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Paget disease of bone 3

Benign:1

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2018

- -

Paget disease of bone 2, early-onset

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Nov 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.18

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over