11-116837053-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5
The NM_000039.3(APOA1):c.148G>A(p.Gly50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,162 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. G50R) has been classified as Pathogenic.
Frequency
Consequence
NM_000039.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOA1 | NM_000039.3 | c.148G>A | p.Gly50Ser | missense_variant | Exon 3 of 4 | ENST00000236850.5 | NP_000030.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251426Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135906
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461838Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13AN XY: 727216
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 50 of the APOA1 protein (p.Gly50Ser). This variant is present in population databases (rs28931574, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with APOA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1773749). 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 APOA1 protein function with a negative predictive value of 95%. This variant disrupts the p.Gly50 amino acid residue in APOA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2123470, 17665932, 21296086, 22952757, 23233678, 27464946). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Cardiovascular phenotype Uncertain:1
The p.G50S variant (also known as c.148G>A), located in coding exon 2 of the APOA1 gene, results from a G to A substitution at nucleotide position 148. The glycine at codon 50 is replaced by serine, 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. 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