rs886039781

Positions:

• chr5-179823864-AAG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003900.5(SQSTM1):​c.311_312del​(p.Glu104ValfsTer48) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SQSTM1 NM_003900.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.73

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-179823864-AAG-A is Pathogenic according to our data. Variant chr5-179823864-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 265781.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.311_312del	p.Glu104ValfsTer48	frameshift_variant	3/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.59_60del	p.Glu20ValfsTer48	frameshift_variant	4/9
SQSTM1	NM_001142299.2	c.59_60del	p.Glu20ValfsTer48	frameshift_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.311_312del	p.Glu104ValfsTer48	frameshift_variant	3/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459676 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Glu104ValfsTer48 variant in SQSTM1 was identified by our study in one individual with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. The p.Glu104ValfsTer48 variant in SQSTM1 has been previously reported in 3 siblings from one family with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (PMID: 27545679) and segregated with disease in this family, but has been identified in 0.000008% (1/125568) of chromosomes by TopMed Bravo (https://bravo.sph.umich.edu/, dbSNP ID: rs748170760). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These previously reported individuals (PMID: 27545679) and the individual identified by our study were homozygotes, which increases the likelihood that the p.Glu104ValfsTer48 variant in SQSTM1 is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265781) and has been interpreted as pathogenic by OMIM. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 104 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SQSTM1 gene is an established disease mechanism in autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3, PP1 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 10, 2016	- -

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: rs886039781; hg19: chr5-179250864;