rs1555881567
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_003073.5(SMARCB1):c.1070C>G(p.Thr357Arg) 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. T357I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003073.5 missense
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.1070C>G | p.Thr357Arg | missense_variant | 8/9 | ENST00000644036.2 | |
SMARCB1 | NM_001362877.2 | c.1124C>G | p.Thr375Arg | missense_variant | 8/9 | ||
SMARCB1 | NM_001317946.2 | c.1097C>G | p.Thr366Arg | missense_variant | 8/9 | ||
SMARCB1 | NM_001007468.3 | c.1043C>G | p.Thr348Arg | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.1070C>G | p.Thr357Arg | missense_variant | 8/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Intellectual disability, autosomal dominant 15 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 21, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMARCB1 related disorder (ClinVar ID: VCV000559897). A different missense change at the same codon (p.Thr357Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000580796). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2019 | The p.T357R variant (also known as c.1070C>G), located in coding exon 8 of the SMARCB1 gene, results from a C to G substitution at nucleotide position 1070. The threonine at codon 357 is replaced by arginine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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