Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000389805.9(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
ENST00000389805.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.73

Publications

2 publications found

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 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

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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: ENST00000389805.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459676

Hom.:

AF XY:

0.00

AC XY:

AN XY:

726174

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60324

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (2)

Neurodegeneration with ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over