19-10985313-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_003072.5(SMARCA4):c.263C>T(p.Pro88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. P88T) has been classified as Uncertain significance.
Frequency
Consequence
NM_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.263C>T | p.Pro88Leu | missense_variant | Exon 3 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.263C>T | p.Pro88Leu | missense_variant | Exon 3 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.263C>T | p.Pro88Leu | missense_variant | Exon 3 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.263C>T | p.Pro88Leu | missense_variant | Exon 4 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.263C>T | p.Pro88Leu | missense_variant | Exon 3 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.263C>T | p.Pro88Leu | missense_variant | Exon 3 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.263C>T | p.Pro88Leu | missense_variant | Exon 4 of 35 | 5 | ENSP00000464778.1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251322Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135900
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727200
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74302
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:3
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the SMARCA4 protein (p.Pro88Leu). This variant is present in population databases (rs371056395, gnomAD 0.02%). 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: 408707). 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) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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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The SMARCA4 c.263C>T (p.Pro88Leu) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with rhabdoid tumor predisposition syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
not provided Uncertain:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28166811) -
The SMARCA4 c.263C>T (p.Pro88Leu) variant has not been reported in individuals with SMARCA4-related conditions in the published literature. The frequency of this variant in the general population, 0.00028 (7/24934 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Intellectual disability, autosomal dominant 16 Uncertain:1
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SMARCA4-related disorder Uncertain:1
The SMARCA4 c.263C>T variant is predicted to result in the amino acid substitution p.Pro88Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11095989-C-T) and it is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408707/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
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