chr12-6845628-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.742G>A(p.Ala248Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,222 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A248S) has been classified 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNB3 | NM_002075.4 | c.742G>A | p.Ala248Thr | missense_variant | 9/10 | ENST00000229264.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNB3 | ENST00000229264.8 | c.742G>A | p.Ala248Thr | missense_variant | 9/10 | 5 | NM_002075.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250678Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135602
GnomAD4 exome AF: 0.0000856 AC: 125AN: 1461032Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54AN XY: 726850
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The c.742G>A (p.A248T) alteration is located in exon 10 (coding exon 8) of the GNB3 gene. This alteration results from a G to A substitution at nucleotide position 742, causing the alanine (A) at amino acid position 248 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2022 | This variant has not been reported in the literature in individuals affected with GNB3-related conditions. This variant is present in population databases (rs372895359, gnomAD 0.05%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 248 of the GNB3 protein (p.Ala248Thr). ClinVar contains an entry for this variant (Variation ID: 1373630). 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. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at