rs201448287
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001048166.1(STIL):c.2132C>T(p.Ser711Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001048166.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000227 AC: 57AN: 251472Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135910
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461876Hom.: 2 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 727242
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 711 of the STIL protein (p.Ser711Leu). This variant is present in population databases (rs201448287, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with STIL-related conditions. ClinVar contains an entry for this variant (Variation ID: 449275). 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: "Possibly Damaging"; 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. -
The S711L variant in the STIL gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S711L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S711L as a variant of uncertain significance. -
Microcephaly 7, primary, autosomal recessive Uncertain:1
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STIL-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at