rs55793208

Positions:

chr5-179833099-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_003900.5(SQSTM1):c.822G>C(p.Glu274Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,614,204 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E274Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 33)

Exomes 𝑓: 0.020 ( 369 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.240

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-179833099-G-Y is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0022973716).

BP6

Variant 5-179833099-G-C is Benign according to our data. Variant chr5-179833099-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 259188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833099-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2343/152324) while in subpopulation NFE AF= 0.0212 (1445/68034). AF 95% confidence interval is 0.0203. There are 32 homozygotes in gnomad4. There are 1068 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SQSTM1	NM_003900.5 linkuse as main transcript	c.822G>C	p.Glu274Asp	missense_variant	6/8	ENST00000389805.9
SQSTM1	NM_001142298.2 linkuse as main transcript	c.570G>C	p.Glu190Asp	missense_variant	7/9
SQSTM1	NM_001142299.2 linkuse as main transcript	c.570G>C	p.Glu190Asp	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.822G>C	p.Glu274Asp	missense_variant	6/8	1	NM_003900.5	P1	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.570G>C	p.Glu190Asp	missense_variant	5/7	1			Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.822G>C	p.Glu274Asp	missense_variant	6/7	5
SQSTM1	ENST00000466342.1 linkuse as main transcript	n.521G>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2347

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00359

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0178

AC:

4480

AN:

251422

Hom.:

AF XY:

0.0189

AC XY:

2570

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.00893

Gnomad ASJ exome

AF:

0.0495

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0201

AC:

29429

AN:

1461880

Hom.:

369

Cov.:

AF XY:

0.0202

AC XY:

14725

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.00932

Gnomad4 ASJ exome

AF:

0.0509

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0168

Gnomad4 FIN exome

AF:

0.0180

Gnomad4 NFE exome

AF:

0.0212

Gnomad4 OTH exome

AF:

0.0222

GnomAD4 genome

AF:

0.0154

AC:

2343

AN:

152324

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1068

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00356

Gnomad4 AMR

AF:

0.0155

Gnomad4 ASJ

AF:

0.0435

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0176

Gnomad4 NFE

AF:

0.0212

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0225

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0253

AC:

218

ExAC

AF:

0.0177

AC:

2153

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0235

EpiControl

AF:

0.0248

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2019	- -

Paget disease of bone 3

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2019

This variant is associated with the following publications: (PMID: 22972638, 25617006, 27275741, 24899140, 23942205, 25681989, 25796131, 15164150, 24042580) -

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

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.0

DANN

Benign

0.69

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.61

T;.;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

M;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.010

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.057

MutPred

0.028

Loss of glycosylation at S276 (P = 0.1499);Loss of glycosylation at S276 (P = 0.1499);.;

MPC

0.12

ClinPred

0.0018

GERP RS

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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