Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_001387283.1(SMARCA4):c.4152G>A(p.Thr1384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,612,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. T1384T) 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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-11035114-G-A is Benign according to our data. Variant chr19-11035114-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212255.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr19-11035114-G-A is described in Lovd as [Likely_benign].
BP7
?
BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-7.86 with no splicing effect.
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000637 (93/1460198) while in subpopulation SAS AF= 0.000882 (76/86166). AF 95% confidence interval is 0.000722. There are 1 homozygotes in gnomad4_exome. There are 66 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jan 13, 2022
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 07, 2016
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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Likely benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Jul 15, 2021
- -
Rhabdoid tumor predisposition syndrome 2 Benign:1
Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
- -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 28, 2020
- -
Coffin-Siris syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -