rs751565055
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001387283.1(SMARCA4):āc.2059A>Gā(p.Lys687Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. K687N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.2059A>G | p.Lys687Glu | missense_variant | 14/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.2059A>G | p.Lys687Glu | missense_variant | 14/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.2059A>G | p.Lys687Glu | missense_variant | 14/36 | NM_001387283.1 | |||
SMARCA4 | ENST00000344626.10 | c.2059A>G | p.Lys687Glu | missense_variant | 14/35 | 1 | NM_003072.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251228Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135780
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461170Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726914
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470278). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs751565055, gnomAD 0.003%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 687 of the SMARCA4 protein (p.Lys687Glu). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Intellectual disability, autosomal dominant 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2023 | The p.K687E variant (also known as c.2059A>G), located in coding exon 13 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2059. The lysine at codon 687 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at