Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_001387283.1(SMARCA4):c.4328G>A(p.Arg1443Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1443W) has been classified as Uncertain significance.
SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Jul 28, 2023
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Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Dec 28, 2023
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1443 of the SMARCA4 protein (p.Arg1443Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 328039). 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 SMARCA4 protein function with a positive 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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Jul 15, 2021
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not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Feb 02, 2022
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as p.R1411Q -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 04, 2021
The c.4328G>A (p.R1443Q) alteration is located in exon 31 (coding exon 30) of the SMARCA4 gene. This alteration results from a G to A substitution at nucleotide position 4328, causing the arginine (R) at amino acid position 1443 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Coffin-Siris syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter