rs1555881563
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003073.5(SMARCB1):c.1066_1067del(p.Leu356AspfsTer4) variant causes a frameshift 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
SMARCB1
NM_003073.5 frameshift
NM_003073.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.66
Genes affected
SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 22-23833648-ACT-A is Pathogenic according to our data. Variant chr22-23833648-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 532963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.1066_1067del | p.Leu356AspfsTer4 | frameshift_variant | 8/9 | ENST00000644036.2 | |
SMARCB1 | NM_001007468.3 | c.1039_1040del | p.Leu347AspfsTer4 | frameshift_variant | 8/9 | ||
SMARCB1 | NM_001317946.2 | c.1093_1094del | p.Leu365AspfsTer4 | frameshift_variant | 8/9 | ||
SMARCB1 | NM_001362877.2 | c.1120_1121del | p.Leu374AspfsTer4 | frameshift_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.1066_1067del | p.Leu356AspfsTer4 | frameshift_variant | 8/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 15 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory Division, Turku University Hospital | Aug 17, 2022 | ACMG class 5: pathogenic (PVS1, PS2, PM2). Variant was absent from parents indicating a de novo origin. The discovered SMARCB1-variant was rare as it was not reported in the Genome Aggregation Database (GnomAD) or in literature. However, this variant was recently reported in Clinical Variant Database as a likely pathogenic variant (ClinVar: VCV000532963.5) - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SMARCB1 protein in which other variant(s) ( p.Thr357Ile, p.Arg374Gln, p.Arg377His) have been determined to be pathogenic (PMID: 22426308, 23906836, 25169651, 26364901; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 532963). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This sequence change creates a premature translational stop signal (p.Leu356Aspfs*4) in the SMARCB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the SMARCB1 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at