rs398122368
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_003073.5(SMARCB1):c.110G>A(p.Arg37His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37P) has been classified as Uncertain significance.
Frequency
Consequence
NM_003073.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.110G>A | p.Arg37His | missense_variant | 2/9 | ENST00000644036.2 | |
SMARCB1 | NM_001362877.2 | c.110G>A | p.Arg37His | missense_variant | 2/9 | ||
SMARCB1 | NM_001317946.2 | c.110G>A | p.Arg37His | missense_variant | 2/9 | ||
SMARCB1 | NM_001007468.3 | c.110G>A | p.Arg37His | missense_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.110G>A | p.Arg37His | missense_variant | 2/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 15 Pathogenic:3Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, University of Torino | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 13, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in a 6-year-old male with global delays, autism spectrum, hypotonia, hydrocephalus, VUR, agenesis of the corpus callosum, myopia, pes cavus, elevated free T4; in an 8-year-old female with intellectual disability, behavior problems, hydrocephalus, dysmorphisms, amblyopia, myopic astigmatixm, hypoplastic labia majora, hypertonia, decreased muscle mass, dysphagia, Wilms tumor - |
Uncertain significance, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Coffin-Siris syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/22726846). - |
SMARCB1-related BAFopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 10, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29907796, 22726846, 25168959) - |
Coffin-Siris syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 16, 2024 | The heterozygous p.Arg37His variant in SMARCB1 was identified by our study in one individual with Coffin-Siris syndrome. The p.Arg37His variant in SMARCB1 has been reported in >10 individuals with Coffin-Siris syndrome (PMIDs: 22726846, 29907796, 33057194, 34906496, 36964972), but was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has been reported in ClinVar (Variation ID: 88893) and has been interpreted as uncertain significance by two submitters, likely pathogenic by two submitters, and pathogenic by three submitters. This variant is assumed de novo in 11 individuals, but maternity and paternity have not been confirmed (PMIDs: 22726846, 29907796, 34906496, 36964972). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in SMARCB1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Coffin-Siris syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Moderate, PP2, PM6, PP3_Moderate (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at