rs1020163987
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_003072.5(SMARCA4):c.1090G>A(p.Val364Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.1090G>A | p.Val364Met | missense_variant | Exon 6 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.1090G>A | p.Val364Met | missense_variant | Exon 6 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.1090G>A | p.Val364Met | missense_variant | Exon 6 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.1090G>A | p.Val364Met | missense_variant | Exon 7 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.1090G>A | p.Val364Met | missense_variant | Exon 6 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.1090G>A | p.Val364Met | missense_variant | Exon 6 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.1090G>A | p.Val364Met | missense_variant | Exon 7 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.502G>A | p.Val168Met | missense_variant | Exon 3 of 32 | ENSP00000496004.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460790Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726652
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 364 of the SMARCA4 protein (p.Val364Met). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408595). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 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. -
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Benign:1
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