12-6841310-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002075.4(GNB3):c.23G>A(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,572 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 (★★).
Frequency
Consequence
NM_002075.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000642 AC: 16AN: 249338Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134896
GnomAD4 exome AF: 0.000140 AC: 205AN: 1461282Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93AN XY: 726858
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74454
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.23G>A (p.R8H) alteration is located in exon 3 (coding exon 1) of the GNB3 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 8 of the GNB3 protein (p.Arg8His). This variant is present in population databases (rs199531660, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GNB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 964467). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNB3 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at