rs769555654
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001387283.1(SMARCA4):c.4235G>A(p.Arg1412His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,602,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 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. R1412C) has been classified as Likely benign.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4235G>A | p.Arg1412His | missense_variant | 30/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.4171-1785G>A | intron_variant | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4235G>A | p.Arg1412His | missense_variant | 30/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.4171-1785G>A | intron_variant | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1450750Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 8AN XY: 721460
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1412 of the SMARCA4 protein (p.Arg1412His). 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: 408635). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 09, 2023 | The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000043 (1/233712 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
SMARCA4-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2024 | The SMARCA4 c.4235G>A variant is predicted to result in the amino acid substitution p.Arg1412His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2023 | 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