rs775807962
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_001387283.1(SMARCA4):c.4256G>A(p.Arg1419His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,596,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4256G>A | p.Arg1419His | missense_variant | 30/36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.4171-1764G>A | intron_variant | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4256G>A | p.Arg1419His | missense_variant | 30/36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000643549.1 | c.4157G>A | p.Arg1386His | missense_variant | 29/35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000344626.10 | c.4171-1764G>A | intron_variant | 1 | NM_003072.5 | ENSP00000343896.4 | ||||
SMARCA4 | ENST00000541122.6 | c.4072-1755G>A | intron_variant | 5 | ENSP00000445036.2 | |||||
SMARCA4 | ENST00000643296.1 | c.4072-1755G>A | intron_variant | ENSP00000496635.1 | ||||||
SMARCA4 | ENST00000644737.1 | c.4072-1755G>A | intron_variant | ENSP00000495548.1 | ||||||
SMARCA4 | ENST00000589677.5 | c.4072-1755G>A | intron_variant | 5 | ENSP00000464778.1 | |||||
SMARCA4 | ENST00000643995.1 | c.3583-1755G>A | intron_variant | ENSP00000496004.1 | ||||||
SMARCA4 | ENST00000644963.1 | c.2815-1755G>A | intron_variant | ENSP00000495599.1 | ||||||
SMARCA4 | ENST00000644065.1 | c.2797-1755G>A | intron_variant | ENSP00000493615.1 | ||||||
SMARCA4 | ENST00000642350.1 | c.2656-1755G>A | intron_variant | ENSP00000495355.1 | ||||||
SMARCA4 | ENST00000643857.1 | c.2524-1755G>A | intron_variant | ENSP00000494159.1 | ||||||
SMARCA4 | ENST00000538456.4 | c.328-1755G>A | intron_variant | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000133 AC: 3AN: 226320Hom.: 0 AF XY: 0.0000161 AC XY: 2AN XY: 123968
GnomAD4 exome AF: 0.00000554 AC: 8AN: 1444706Hom.: 0 Cov.: 28 AF XY: 0.00000557 AC XY: 4AN XY: 718290
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 05, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1419 of the SMARCA4 protein (p.Arg1419His). 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: 328037). 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2022 | 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. - |
Coffin-Siris syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at