1-47251165-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001048166.1(STIL):c.3838C>T(p.Arg1280Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,628 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1280H) has been classified as Likely benign.
Frequency
Consequence
NM_001048166.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000440 AC: 11AN: 250100Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135110
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461462Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30AN XY: 726986
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Microcephaly 7, primary, autosomal recessive Pathogenic:1Uncertain:1
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not provided Pathogenic:1Uncertain:1
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1279 of the STIL protein (p.Arg1279Cys). This variant is present in population databases (rs199634446, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of primary microcephaly (PMID: 24986681, 26633542, 33132204). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg1280Cys. ClinVar contains an entry for this variant (Variation ID: 502127). 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 expected to disrupt STIL protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at