5-179836442-AC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003900.5(SQSTM1):c.1175del(p.Pro392ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SQSTM1 NM_003900.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0140

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]

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-179836442-AC-A is Pathogenic according to our data. Variant chr5-179836442-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2136359.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.1175del	p.Pro392ArgfsTer3	frameshift_variant	8/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.923del	p.Pro308ArgfsTer3	frameshift_variant	9/9
SQSTM1	NM_001142299.2	c.923del	p.Pro308ArgfsTer3	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1175del	p.Pro392ArgfsTer3	frameshift_variant	8/8	1	NM_003900.5	P1
SQSTM1	ENST00000360718.5	c.923del	p.Pro308ArgfsTer3	frameshift_variant	7/7	1
MRNIP	ENST00000522663.5	c.*1247del		3_prime_UTR_variant, NMD_transcript_variant	9/9	1
SQSTM1	ENST00000510187.5	c.951-26del		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2022

This sequence change creates a premature translational stop signal (p.Pro392Argfs*3) in the SQSTM1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the SQSTM1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Paget’s disease of bone (PMID: 14584883). This variant is also known as 1215delC. This variant disrupts the region of the SQSTM1 protein between codon 391 and 396. Other variants in this region have been observed in individuals with autosomal dominant SQSTM1-related conditions (PMID: 12374763, 14584883, 25664955), which suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179263442;