5-179836447-CGGCTGATTGAGTCCCTCTCCCAGATGCTGTCCATGGGCTTCTCTGATGAAGGCGGCTGGCTCACCAGGCTCCTGCAGACCAAGAACTATGACATCGGAGCGGCTCTGGACACCATCCAGTATTCAAAGCATCCCCCGCCGTTGTGACCACTTTTGCCCACCTCTTCTGCGTGCCCCTCTTCTGTCTCATAGTTGTGTTAAGCTTGCGTAGAATTGCAGGTCTCTGTACGGGCCAGTTTCTCTGCCTTCTTCCAGGATCAGGGGTTAGGGTGCAAGAAGCCATTTAGGGCAGCAAAACAAGTGACATGAAGGGAGGGTCCCTGTGTGTGTGTGTGCTGATGTTTCCTGGGTGCCCTGGCTCCTTGCAGCAGGGCTGGGCCTGCGAGACCCAAGGCTCACTGCAGCGCGCTCCTGACCCCTCCCTGCAGGGGCTACGTTAGCAGCCCAGCACATAGCTTGCCTAATGGCTTTCACTTTCTCTTTTGTTTTAAATGACTCATAGGTCCCTGACATTTAGTTGATTATTTTCTGCTACAGACCTGGTACACTCTGATTTTAGATAAAGTAAGCCTAGGTGTTGTCAGCAGGCAGGCTGGGGAGGCCAGTGTTGTGGGCTTCCTGCTGGGACTGAGAAGGCTCACGAAGGGCATCCGCAATGTTGGTTTCACTGAGAGCTGCCTCCTGGTCTCTTCACCACTGTAGTTCTCTCATTTCCAAACCATCAGCTGCTTTTAAAATAAGATCTCTTTGTAGCCATCCTGTTAAATTTGTAAACAATCTAATTAAAT-C

Variant names:

• chr5-179836447-CGGCTGATTGAGTCCCTCTCCCAGATGCTGTCCATGGGCTTCTCTGATGAAGGCGGCTGGCTCACCAGGCTCCTGCAGACCAAGAACTATGACATCGGAGCGGCTCTGGACACCATCCAGTATTCAAAGCATCCCCCGCCGTTGTGACCACTTTTGCCCACCTCTTCTGCGTGCCCCTCTTCTGTCTCATAGTTGTGTTAAGCTTGCGTAGAATTGCAGGTCTCTGTACGGGCCAGTTTCTCTGCCTTCTTCCAGGATCAGGGGTTAGGGTGCAAGAAGCCATTTAGGGCAGCAAAACAAGTGACATGAAGGGAGGGTCCCTGTGTGTGTGTGTGCTGATGTTTCCTGGGTGCCCTGGCTCCTTGCAGCAGGGCTGGGCCTGCGAGACCCAAGGCTCACTGCAGCGCGCTCCTGACCCCTCCCTGCAGGGGCTACGTTAGCAGCCCAGCACATAGCTTGCCTAATGGCTTTCACTTTCTCTTTTGTTTTAAATGACTCATAGGTCCCTGACATTTAGTTGATTATTTTCTGCTACAGACCTGGTACACTCTGATTTTAGATAAAGTAAGCCTAGGTGTTGTCAGCAGGCAGGCTGGGGAGGCCAGTGTTGTGGGCTTCCTGCTGGGACTGAGAAGGCTCACGAAGGGCATCCGCAATGTTGGTTTCACTGAGAGCTGCCTCCTGGTCTCTTCACCACTGTAGTTCTCTCATTTCCAAACCATCAGCTGCTTTTAAAATAAGATCTCTTTGTAGCCATCCTGTTAAATTTGTAAACAATCTAATTAAAT-C
• NM_003900.5:c.1181_*644del

Variant summary

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

The NM_003900.5(SQSTM1):​c.1181_*644del​(p.Leu394HisfsTer7) variant causes a frameshift, stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SQSTM1 NM_003900.5 frameshift, stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-179836447-CGGCTGATTGAGTCCCTCTCCCAGATGCTGTCCATGGGCTTCTCTGATGAAGGCGGCTGGCTCACCAGGCTCCTGCAGACCAAGAACTATGACATCGGAGCGGCTCTGGACACCATCCAGTATTCAAAGCATCCCCCGCCGTTGTGACCACTTTTGCCCACCTCTTCTGCGTGCCCCTCTTCTGTCTCATAGTTGTGTTAAGCTTGCGTAGAATTGCAGGTCTCTGTACGGGCCAGTTTCTCTGCCTTCTTCCAGGATCAGGGGTTAGGGTGCAAGAAGCCATTTAGGGCAGCAAAACAAGTGACATGAAGGGAGGGTCCCTGTGTGTGTGTGTGCTGATGTTTCCTGGGTGCCCTGGCTCCTTGCAGCAGGGCTGGGCCTGCGAGACCCAAGGCTCACTGCAGCGCGCTCCTGACCCCTCCCTGCAGGGGCTACGTTAGCAGCCCAGCACATAGCTTGCCTAATGGCTTTCACTTTCTCTTTTGTTTTAAATGACTCATAGGTCCCTGACATTTAGTTGATTATTTTCTGCTACAGACCTGGTACACTCTGATTTTAGATAAAGTAAGCCTAGGTGTTGTCAGCAGGCAGGCTGGGGAGGCCAGTGTTGTGGGCTTCCTGCTGGGACTGAGAAGGCTCACGAAGGGCATCCGCAATGTTGGTTTCACTGAGAGCTGCCTCCTGGTCTCTTCACCACTGTAGTTCTCTCATTTCCAAACCATCAGCTGCTTTTAAAATAAGATCTCTTTGTAGCCATCCTGTTAAATTTGTAAACAATCTAATTAAAT-C is Pathogenic according to our data. Variant chr5-179836447-CGGCTGATTGAGTCCCTCTCCCAGATGCTGTCCATGGGCTTCTCTGATGAAGGCGGCTGGCTCACCAGGCTCCTGCAGACCAAGAACTATGACATCGGAGCGGCTCTGGACACCATCCAGTATTCAAAGCATCCCCCGCCGTTGTGACCACTTTTGCCCACCTCTTCTGCGTGCCCCTCTTCTGTCTCATAGTTGTGTTAAGCTTGCGTAGAATTGCAGGTCTCTGTACGGGCCAGTTTCTCTGCCTTCTTCCAGGATCAGGGGTTAGGGTGCAAGAAGCCATTTAGGGCAGCAAAACAAGTGACATGAAGGGAGGGTCCCTGTGTGTGTGTGTGCTGATGTTTCCTGGGTGCCCTGGCTCCTTGCAGCAGGGCTGGGCCTGCGAGACCCAAGGCTCACTGCAGCGCGCTCCTGACCCCTCCCTGCAGGGGCTACGTTAGCAGCCCAGCACATAGCTTGCCTAATGGCTTTCACTTTCTCTTTTGTTTTAAATGACTCATAGGTCCCTGACATTTAGTTGATTATTTTCTGCTACAGACCTGGTACACTCTGATTTTAGATAAAGTAAGCCTAGGTGTTGTCAGCAGGCAGGCTGGGGAGGCCAGTGTTGTGGGCTTCCTGCTGGGACTGAGAAGGCTCACGAAGGGCATCCGCAATGTTGGTTTCACTGAGAGCTGCCTCCTGGTCTCTTCACCACTGTAGTTCTCTCATTTCCAAACCATCAGCTGCTTTTAAAATAAGATCTCTTTGTAGCCATCCTGTTAAATTTGTAAACAATCTAATTAAAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2951682.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1181_*644del	p.Leu394HisfsTer7	frameshift_variant, stop_lost	Exon 8 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_003900.5	c.1181_*644del		3_prime_UTR_variant	Exon 8 of 8	ENST00000389805.9	NP_003891.1
MRNIP	NM_016175.4	c.*157_*943del		downstream_gene_variant		ENST00000292586.11	NP_057259.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1181_*644del	p.Leu394HisfsTer7	frameshift_variant, stop_lost	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000389805.9	c.1181_*644del		3_prime_UTR_variant	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4
MRNIP	ENST00000292586.11	c.*157_*943del		downstream_gene_variant		1	NM_016175.4	ENSP00000292586.6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu394Hisfs*7) in the SQSTM1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the SQSTM1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SQSTM1-related conditions. This variant is located in a region of the SQSTM1 protein where a significant number of SQSTM1 nonsense and frameshift mutations have been reported in association with autosomal dominant SQSTM1-associated Paget disease of bone (PMID: 16813535, 14584883, 12374763, 25664955). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr5-179263447;