5-179821119-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003900.5(SQSTM1):c.183C>T(p.Gly61Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,380,634 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0037 ( 10 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.49

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=-0.48).

BP6

Variant 5-179821119-C-T is Benign according to our data. Variant chr5-179821119-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 353157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179821119-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00289 (440/152000) while in subpopulation NFE AF= 0.00449 (305/67912). AF 95% confidence interval is 0.00408. There are 0 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.183C>T	p.Gly61Gly	synonymous_variant	Exon 1 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.-47-1839C>T		intron_variant	Intron 2 of 8		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.-47-1839C>T		intron_variant	Intron 2 of 8		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 link	c.183C>T	p.Gly61Gly	synonymous_variant	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

440

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00520

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00870

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00449

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00432

AC:

110

AN:

25480

Hom.:

AF XY:

0.00449

AC XY:

AN XY:

15830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000250

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.00507

Gnomad OTH exome

AF:

0.00272

GnomAD4 exome

AF:

0.00373

AC:

4588

AN:

1228634

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

2231

AN XY:

596978

show subpopulations

Gnomad4 AFR exome

AF:

0.000284

Gnomad4 AMR exome

AF:

0.000572

Gnomad4 ASJ exome

AF:

0.00556

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00157

Gnomad4 FIN exome

AF:

0.00720

Gnomad4 NFE exome

AF:

0.00398

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.00289

AC:

440

AN:

152000

Hom.:

Cov.:

AF XY:

0.00315

AC XY:

234

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00520

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00870

Gnomad4 NFE

AF:

0.00449

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00396

Hom.:

Bravo

AF:

0.00206

Asia WGS

AF:

0.000580

AC:

AN:

3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25796131, 22084127) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SQSTM1: BP4, BP7 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Paget disease of bone 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.94

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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