rs768379745
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_003073.5(SMARCB1):c.673G>A(p.Asp225Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D225Y) 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.673G>A | p.Asp225Asn | missense_variant | 6/9 | ENST00000644036.2 | |
SMARCB1 | NM_001362877.2 | c.727G>A | p.Asp243Asn | missense_variant | 6/9 | ||
SMARCB1 | NM_001317946.2 | c.700G>A | p.Asp234Asn | missense_variant | 6/9 | ||
SMARCB1 | NM_001007468.3 | c.646G>A | p.Asp216Asn | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCB1 | ENST00000644036.2 | c.673G>A | p.Asp225Asn | missense_variant | 6/9 | NM_003073.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251416Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461704Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727176
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 1041054). This variant has not been reported in the literature in individuals affected with SMARCB1-related conditions. This variant is present in population databases (rs768379745, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 225 of the SMARCB1 protein (p.Asp225Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at