chr19-10991285-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001387283.1(SMARCA4):āc.1381A>Cā(p.Lys461Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,256 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K461R) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.1381A>C | p.Lys461Gln | missense_variant | 8/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.1381A>C | p.Lys461Gln | missense_variant | 8/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.1381A>C | p.Lys461Gln | missense_variant | 8/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.1381A>C | p.Lys461Gln | missense_variant | 8/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240598Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130462
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458256Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725064
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2022 | 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470240). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs757516325, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 461 of the SMARCA4 protein (p.Lys461Gln). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2023 | The p.K461Q variant (also known as c.1381A>C), located in coding exon 7 of the SMARCA4 gene, results from an A to C substitution at nucleotide position 1381. The lysine at codon 461 is replaced by glutamine, 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 tolerated 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