rs886039781

Variant names:

• chr5-179823864-AAG-A
• rs886039781
• NM_003900.5:c.311_312delAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003900.5(SQSTM1):​c.311_312delAG​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. E104E) has been classified as Likely benign. 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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.73
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 VariationId is 265781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	NM_003900.5	MANE Select	c.311_312delAG	p.Glu104ValfsTer48	frameshift	Exon 3 of 8	NP_003891.1
	SQSTM1	NM_001142298.2		c.59_60delAG	p.Glu20ValfsTer48	frameshift	Exon 4 of 9	NP_001135770.1
	SQSTM1	NM_001142299.2		c.59_60delAG	p.Glu20ValfsTer48	frameshift	Exon 4 of 9	NP_001135771.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.311_312delAG	p.Glu104ValfsTer48	frameshift	Exon 3 of 8	ENSP00000374455.4
	SQSTM1	ENST00000360718.5	TSL:1	c.59_60delAG	p.Glu20ValfsTer48	frameshift	Exon 2 of 7	ENSP00000353944.5
	SQSTM1	ENST00000510187.5	TSL:5	c.311_312delAG	p.Glu104ValfsTer48	frameshift	Exon 3 of 7	ENSP00000424477.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5346

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 10, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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).

Neurodegeneration with ataxia Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PP1,PM3,PM2

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039781; hg19: chr5-179250864;