rs141826721
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2PP2PP3BS2
The NM_001387283.1(SMARCA4):c.4861G>A(p.Glu1621Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1621D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4861G>A | p.Glu1621Lys | missense_variant | 34/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.4765G>A | p.Glu1589Lys | missense_variant | 33/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4861G>A | p.Glu1621Lys | missense_variant | 34/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.4765G>A | p.Glu1589Lys | missense_variant | 33/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248550Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134588
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461522Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727054
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1621 of the SMARCA4 protein (p.Glu1621Lys). This variant is present in population databases (rs141826721, gnomAD 0.0009%). 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: 408696). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 | Jan 10, 2024 | The p.E1621K variant (also known as c.4861G>A), located in coding exon 33 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4861. The glutamic acid at codon 1621 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at