rs1256465004
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_001387283.1(SMARCA4):c.2858A>G(p.Lys953Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001387283.1 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.2858A>G | p.Lys953Arg | missense_variant, splice_region_variant | 19/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.2858A>G | p.Lys953Arg | missense_variant, splice_region_variant | 19/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.2858A>G | p.Lys953Arg | missense_variant, splice_region_variant | 19/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.2858A>G | p.Lys953Arg | missense_variant, splice_region_variant | 19/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249532Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134990
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459498Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726056
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 953 of the SMARCA4 protein (p.Lys953Arg). 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: 470322). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2024 | The p.K953R variant (also known as c.2858A>G), located in coding exon 18 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2858. The lysine at codon 953 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this variant is inconclusive.. Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at