rs748441485
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PP2PP3_ModerateBP6BS1BS2
The NM_003073.5(SMARCB1):c.1022G>A(p.Arg341Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R341W) 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_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCB1 | NM_003073.5 | c.1022G>A | p.Arg341Gln | missense_variant | 8/9 | ENST00000644036.2 | |
SMARCB1 | NM_001362877.2 | c.1076G>A | p.Arg359Gln | missense_variant | 8/9 | ||
SMARCB1 | NM_001317946.2 | c.1049G>A | p.Arg350Gln | missense_variant | 8/9 | ||
SMARCB1 | NM_001007468.3 | c.995G>A | p.Arg332Gln | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.1022G>A | p.Arg341Gln | missense_variant | 8/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 341 of the SMARCB1 protein (p.Arg341Gln). This variant is present in population databases (rs748441485, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532966). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCB1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at