rs752009611

Variant names:

• chr5-179833111-AGAG-A
• rs752009611
• NM_003900.5:c.838_840delGAG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_003900.5(SQSTM1):​c.838_840delGAG​(p.Glu280del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.48

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003900.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-179833111-AGAG-A is Benign according to our data. Variant chr5-179833111-AGAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475406.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000217 (33/152348) while in subpopulation AFR AF= 0.000649 (27/41580). AF 95% confidence interval is 0.000458. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.838_840delGAG	p.Glu280del	conservative_inframe_deletion	Exon 6 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.586_588delGAG	p.Glu196del	conservative_inframe_deletion	Exon 7 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.586_588delGAG	p.Glu196del	conservative_inframe_deletion	Exon 7 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.838_840delGAG	p.Glu280del	conservative_inframe_deletion	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.586_588delGAG	p.Glu196del	conservative_inframe_deletion	Exon 5 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.838_840delGAG	p.Glu280del	conservative_inframe_deletion	Exon 6 of 7	5		ENSP00000424477.1
SQSTM1	ENST00000466342.1	n.537_539delGAG		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251410 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135894

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461892 Hom.: 0 AF XY: 0.0000536 AC XY: 39 AN XY: 727246

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74500

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000280

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 21, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with FTLD and progressive supranuclear palsy in the published literature (van der Zee et al., 2014); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24899140) -

SQSTM1-related disorder Uncertain:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SQSTM1 c.838_840delGAG variant is predicted to result in an in-frame deletion (p.Glu280del). This variant has been reported in an individual with frontotemporal lobar degeneration (van der Zee et al. 2014. PubMed ID: 24899140) and in an individual with amyotrophic lateral sclerosis (Leighton et al. 2022. PubMed ID: 36515702). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.838_840del, results in the deletion of 1 amino acid(s) of the SQSTM1 protein (p.Glu280del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752009611, gnomAD 0.05%). This variant has been observed in individual(s) with clinical features of SQSTM1-related conditions (PMID: 24899140, 36515702). ClinVar contains an entry for this variant (Variation ID: 475406). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs752009611; hg19: chr5-179260111;