rs10058037

Positions:

chr5-179833661-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003900.5(SQSTM1):c.1044G>A(p.Pro348=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,614,078 control chromosomes in the GnomAD database, including 472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 239 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 233 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.56

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 5-179833661-G-A is Benign according to our data. Variant chr5-179833661-G-A is described in ClinVar as [Benign]. Clinvar id is 259187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SQSTM1	NM_003900.5 linkuse as main transcript	c.1044G>A	p.Pro348=	synonymous_variant	7/8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.792G>A	p.Pro264=	synonymous_variant	8/9		NP_001135770.1
SQSTM1	NM_001142299.2 linkuse as main transcript	c.792G>A	p.Pro264=	synonymous_variant	8/9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.1044G>A	p.Pro348=	synonymous_variant	7/8	1	NM_003900.5	ENSP00000374455	P1	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.792G>A	p.Pro264=	synonymous_variant	6/7	1		ENSP00000353944		Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+434G>A		intron_variant		5		ENSP00000424477

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4608

AN:

152074

Hom.:

237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00963

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.00741

AC:

1863

AN:

251428

Hom.:

AF XY:

0.00538

AC XY:

731

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.00399

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00356

AC:

5204

AN:

1461886

Hom.:

233

Cov.:

AF XY:

0.00302

AC XY:

2198

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.00465

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000674

Gnomad4 OTH exome

AF:

0.00765

GnomAD4 genome

AF:

0.0304

AC:

4625

AN:

152192

Hom.:

239

Cov.:

AF XY:

0.0299

AC XY:

2227

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.00962

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000574

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0335

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Jan 13, 2021	- -

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 30, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.13

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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