NM_001387283.1:c.365C>T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001387283.1(SMARCA4):c.365C>T(p.Ser122Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S122P) 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 -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.365C>T | p.Ser122Leu | missense_variant | Exon 4 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.365C>T | p.Ser122Leu | missense_variant | Exon 4 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.365C>T | p.Ser122Leu | missense_variant | Exon 4 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.365C>T | p.Ser122Leu | missense_variant | Exon 5 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.365C>T | p.Ser122Leu | missense_variant | Exon 4 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.365C>T | p.Ser122Leu | missense_variant | Exon 4 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.365C>T | p.Ser122Leu | missense_variant | Exon 5 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.-224C>T | upstream_gene_variant | ENSP00000496004.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461462Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727070
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
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This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 122 of the SMARCA4 protein (p.Ser122Leu). This variant is not present in population databases (gnomAD no frequency). 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: 484861). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 80%. 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. -
Intellectual disability, autosomal dominant 16 Uncertain:1
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Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16;C5935610:Otosclerosis 12 Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.S122L variant (also known as c.365C>T), located in coding exon 3 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 365. The serine at codon 122 is replaced by leucine, an amino acid with dissimilar properties. 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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