Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_001387283.1(SMARCA4):c.2936G>A(p.Arg979Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R979R) 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 Pathogenic. Variant got 10 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001387283.1
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, 0.985
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-11023594-G-A is Pathogenic according to our data. Variant chr19-11023594-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212246.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, Likely_pathogenic=2}. Variant chr19-11023594-G-A is described in Lovd as [Pathogenic].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
May 06, 2021
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease is not clearly established for Coffin-Siris syndrome 4 (MIM#614609). However, susceptibility to rhabdoid tumor predisposition syndrome 2 (MIM#613325) is caused by loss of function variants (OMIM, PMID: 22426308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported mostly as likely pathogenic and pathogenic, and has been observed in multiple de novo individuals with Coffin-Siris syndrome, intellectual disability and/or cleft palate (Decipher, ClinVar, PMID: 28973083). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Sep 27, 2018
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported as a de novo change in a male with Coffin Siri syndrome [PMID:28973083] -
Pathogenic, criteria provided, single submitter
clinical testing
Daryl Scott Lab, Baylor College of Medicine
Nov 11, 2020
- -
Likely pathogenic, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Jul 15, 2021
- -
Cleft palate Pathogenic:1
Likely pathogenic, no assertion criteria provided
clinical testing
Autoinflammatory diseases unit, CHU de Montpellier
Likely pathogenic, criteria provided, single submitter
clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon
Jan 05, 2018
- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Mar 02, 2022
De novo variant with confirmed parentage in a critically ill infant, but no clinical information provided (Meng et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28973083, 32686290, 24658002, 33144586, 34930489) -
SMARCA4-related BAFopathy Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Jun 10, 2021
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago