rs1057517825
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_003073.5(SMARCB1):c.1121G>A(p.Arg374Gln) variant causes a missense, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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. R374W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003073.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.1121G>A | p.Arg374Gln | missense_variant, splice_region_variant | 9/9 | ENST00000644036.2 | |
SMARCB1 | NM_001362877.2 | c.1175G>A | p.Arg392Gln | missense_variant, splice_region_variant | 9/9 | ||
SMARCB1 | NM_001317946.2 | c.1148G>A | p.Arg383Gln | missense_variant, splice_region_variant | 9/9 | ||
SMARCB1 | NM_001007468.3 | c.1094G>A | p.Arg365Gln | missense_variant, splice_region_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.1121G>A | p.Arg374Gln | missense_variant, splice_region_variant | 9/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1438640Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 713658
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 15 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 13, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2021 | Reported in an adult male in published literature with Coffin-Siris syndrome and schwannomatosis (Gossai et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11104031, 23091298, 23525077, 31216405, 23906836, 31273213, 26364901) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the SMARCB1 protein (p.Arg374Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 23906836, 26364901, 31273213; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372511). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
SMARCB1-related BAFopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 10, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2017 | The p.R374Q variant (also known as c.1121G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with Coffin-Siris syndrome (Wieczorek D et al. Hum. Mol. Genet., 2013 Dec;22:5121-35; Kosho T et al. Am J Med Genet C Semin Med Genet, 2014 Sep;166C:262-75; Gossai N et al. Am. J. Med. Genet. A, 2015 Dec;167A:3186-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at