chrX-123184537-T-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PVS1_SupportingBS2
The NM_007325.5(GRIA3):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,090,266 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007325.5 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRIA3 | NM_000828.5 | c.2T>C | p.Met1? | start_lost | Exon 1 of 16 | ENST00000622768.5 | NP_000819.4 | |
GRIA3 | NM_007325.5 | c.2T>C | p.Met1? | start_lost | Exon 1 of 16 | ENST00000620443.2 | NP_015564.5 | |
GRIA3 | NM_001256743.2 | c.2T>C | p.Met1? | start_lost | Exon 1 of 4 | NP_001243672.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 20
GnomAD3 exomes AF: 0.0000273 AC: 5AN: 183430Hom.: 0 AF XY: 0.0000295 AC XY: 2AN XY: 67906
GnomAD4 exome AF: 0.0000147 AC: 16AN: 1090266Hom.: 0 Cov.: 29 AF XY: 0.0000168 AC XY: 6AN XY: 356216
GnomAD4 genome Cov.: 20
ClinVar
Submissions by phenotype
not provided Uncertain:4
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This sequence change affects the initiator methionine of the GRIA3 mRNA. The next in-frame methionine is located at codon 7. This variant is present in population databases (rs752728469, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 624438). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
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Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34426522, 28152038) -
Inborn genetic diseases Pathogenic:1
The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the GRIA3 gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the native initiation codon. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and possibly absence of protein translation. However, this amino acid position is not well conserved and a number of species do not have the initiation codon at this position. Furthermore, another ATG that is highly conserved among species is located down stream. The ATG sequence, located six amino acids down stream from the human reference sequence, is purported to function as the start site for rat GluR3 based on cDNA studies (Rampersad, V et al. Biochim Biophys Acta 1994;1219:563-6). In humans, iontropic flutamate receptors (iGluR) are purported to contain a short signal peptide (between 14-33 amino acids long) at the N-terminus that targets the protein to the cell membrane and mislocalization may disuprt neuronal function (Traynelis SF, Pharmacol. Rev. 2010 Sep; 62(3):405-96). It is anticipated that the p.M1? alteration, would result in the shortening of the signal peptide and lead to mislocalization of the hGluR3 protein; however direct evidence on this alteration's affect on transport to the cell membrane is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at