rs1555875892
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003073.5(SMARCB1):c.137_140dup(p.Tyr47Ter) 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 (★). 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: 3.12
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 12 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 22-23791797-G-GAGAT is Pathogenic according to our data. Variant chr22-23791797-G-GAGAT is described in ClinVar as [Pathogenic]. Clinvar id is 464322.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.137_140dup | p.Tyr47Ter | frameshift_variant | 2/9 | ENST00000644036.2 | |
SMARCB1 | NM_001007468.3 | c.137_140dup | p.Tyr47Ter | frameshift_variant | 2/9 | ||
SMARCB1 | NM_001317946.2 | c.137_140dup | p.Tyr47Ter | frameshift_variant | 2/9 | ||
SMARCB1 | NM_001362877.2 | c.137_140dup | p.Tyr47Ter | frameshift_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.137_140dup | p.Tyr47Ter | frameshift_variant | 2/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2017 | For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SMARCB1 are known to be pathogenic (PMID: 10521299, 21208904). A different variant, c.141C>A, with the same effect (p.Tyr47*) has been reported in an individual with rhabdoid tumors (PMID: 21108436). This sequence change inserts 4 nucleotides in exon 2 of the SMARCB1 mRNA (c.137_140dupGATA), causing a frameshift at codon 47. This creates a premature translational stop signal (p.Tyr47*) and is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at