rs148530368
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_003072.5(SMARCA4):c.1076G>A(p.Arg359Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,612,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 6 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 6 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 6 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 7 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 6 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 6 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 7 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.488G>A | p.Arg163Gln | missense_variant | Exon 3 of 32 | ENSP00000496004.1 |
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000187 AC: 45AN: 241264Hom.: 0 AF XY: 0.000175 AC XY: 23AN XY: 131646
GnomAD4 exome AF: 0.000377 AC: 551AN: 1460698Hom.: 0 Cov.: 34 AF XY: 0.000352 AC XY: 256AN XY: 726620
GnomAD4 genome AF: 0.000210 AC: 32AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74474
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
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SMARCA4: PP2, BS1 -
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including acute lymphoblastic leukemia (ALL) and other cancers (Zhang 2015, Wang 2017); This variant is associated with the following publications: (PMID: 26580448, 26353884, 23718828, 27363283) -
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Hereditary cancer-predisposing syndrome Benign:2
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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. -
Intellectual disability, autosomal dominant 16 Benign:1
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Rhabdoid tumor predisposition syndrome 2 Benign:1
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Coffin-Siris syndrome Benign:1
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. -
SMARCA4-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at