NM_003073.5:c.*82C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_003073.5(SMARCB1):c.*82C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,288,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_003073.5 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.*82C>T | 3_prime_UTR_variant | Exon 9 of 9 | ENST00000644036.2 | NP_003064.2 | ||
SMARCB1 | NM_001362877.2 | c.*82C>T | 3_prime_UTR_variant | Exon 9 of 9 | NP_001349806.1 | |||
SMARCB1 | NM_001317946.2 | c.*82C>T | 3_prime_UTR_variant | Exon 9 of 9 | NP_001304875.1 | |||
SMARCB1 | NM_001007468.3 | c.*82C>T | 3_prime_UTR_variant | Exon 9 of 9 | NP_001007469.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 7.76e-7 AC: 1AN: 1288604Hom.: 0 Cov.: 20 AF XY: 0.00000156 AC XY: 1AN XY: 640946
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; however, transcript analysis found that SMARCB1 c.*82C>T did not induce abnormal splicing, but the variant was associated with reduced expression (Smith 2012b); This variant is associated with the following publications: (PMID: 22949514, 18647326, 19582488, 19320657, 25631985, 27921248, 25857641, 22434358, 28365909, 24933152) -
This variant occurs in a non-coding region of the SMARCB1 gene. It does not change the encoded amino acid sequence of the SMARCB1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with schwannomatosis (PMID: 18647326, 22434358, 24933152). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 239481). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SMARCB1 function (PMID: 22949514). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
Schwannoma;C4024276:Peripheral schwannoma Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.*82C>T pathogenic mutation is located in the 3' untranslated region (3’ UTR) of the SMARCB1 gene. This variant results from a C to T substitution 82 nucleotides downstream of the last translated codon. This variant has been observed in multiple individuals with diagnosed with schwannomatosis (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Smith MJ et al. Neurogenetics, 2012 May;13:141-5; Smith MJ et al. Cancer Genet, 2014 Sep;207:373-8; Piotrowski A et al. Hum Mutat, 2022 Jan;43:74-84). It has also been reported to segregate with disease in related individuals (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Asai K et al. Brain Tumor Pathol, 2015 Jul;32:216-20). This alteration is reported to have reduced expression of the SMARCB1 transcript compared to the wild-type (Smith MJ et al. Hum Mol Genet, 2012 Dec;21:5239-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for SMARCB1-related schwannomatosis and tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown. -
SMARCB1-related schwannomatosis Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at