Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001387283.1(SMARCA4):c.3525C>G(p.Asp1175Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1175D) has been classified as Likely benign.
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]
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, SMARCA4
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.939
Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);Loss of glycosylation at S1176 (P = 0.1756);.;Loss of glycosylation at S1176 (P = 0.1756);.;.;.;