5-179821119-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003900.5(SQSTM1):c.183C>T(p.Gly61=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G61G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -17 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.
• BS2: High AC in GnomAd at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.183C>T	p.Gly61=	synonymous_variant	1/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.-47-1839C>T		intron_variant
SQSTM1	NM_001142299.2	c.-47-1839C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.183C>T	p.Gly61=	synonymous_variant	1/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 440 AN: 151892 Hom.: 0 Cov.: 34

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.: 1 AF XY: 0.00449 AC XY: 71 AN XY: 15830

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.: 10 Cov.: 31 AF XY: 0.00374 AC XY: 2231 AN XY: 596978

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.: 0 Cov.: 34 AF XY: 0.00315 AC XY: 234 AN XY: 74302

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.: 1

Bravo AF: 0.00206

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2019	This variant is associated with the following publications: (PMID: 25796131, 22084127) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SQSTM1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
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

Other links and lift over

dbSNP: rs767340839; hg19: chr5-179248119;