X-123184575-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_007325.5(GRIA3):c.40G>A(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,208,068 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007325.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRIA3 | NM_000828.5 | c.40G>A | p.Ala14Thr | missense_variant | Exon 1 of 16 | ENST00000622768.5 | NP_000819.4 | |
GRIA3 | NM_007325.5 | c.40G>A | p.Ala14Thr | missense_variant | Exon 1 of 16 | ENST00000620443.2 | NP_015564.5 | |
GRIA3 | NM_001256743.2 | c.40G>A | p.Ala14Thr | missense_variant | Exon 1 of 4 | NP_001243672.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRIA3 | ENST00000620443.2 | c.40G>A | p.Ala14Thr | missense_variant | Exon 1 of 16 | 1 | NM_007325.5 | ENSP00000478489.1 | ||
GRIA3 | ENST00000622768.5 | c.40G>A | p.Ala14Thr | missense_variant | Exon 1 of 16 | 5 | NM_000828.5 | ENSP00000481554.1 |
Frequencies
GnomAD3 genomes AF: 0.00000902 AC: 1AN: 110837Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 33021
GnomAD4 exome AF: 0.00000911 AC: 10AN: 1097231Hom.: 0 Cov.: 29 AF XY: 0.00000827 AC XY: 3AN XY: 362597
GnomAD4 genome AF: 0.00000902 AC: 1AN: 110837Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 33021
ClinVar
Submissions by phenotype
not provided Uncertain:2
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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 985615). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 14 of the GRIA3 protein (p.Ala14Thr). -
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Inborn genetic diseases Uncertain:1
The alteration results in an amino acid change:_x000D_ _x000D_ The c.40G>A (p.A14T) alteration is located in coding exon 1 of the GRIA3 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a threonine (T). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GRIA3 c.40G>A alteration was not observed, with coverage at this position. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.A14 amino acid is not conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.A14T alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at