chr5-151822698-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000171.4(GLRA1):c.1325G>A(p.Arg442His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R442C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000171.4 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.1325G>A | p.Arg442His | missense_variant | 9/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.1349G>A | p.Arg450His | missense_variant | 9/9 | ||
GLRA1 | NM_001292000.2 | c.1076G>A | p.Arg359His | missense_variant | 8/8 | ||
GLRA1 | XM_047417105.1 | c.1373G>A | p.Arg458His | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.1325G>A | p.Arg442His | missense_variant | 9/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.1349G>A | p.Arg450His | missense_variant | 9/9 | 1 | A1 | ||
GLRA1 | ENST00000462581.6 | c.*1083G>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/8 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152118Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251238Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135780
GnomAD4 exome AF: 0.0000671 AC: 98AN: 1460988Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49AN XY: 726888
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5AN XY: 74432
ClinVar
Submissions by phenotype
Hyperekplexia 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Oct 08, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2022 | Reported in a patient with hyperekplexia; however evidence in support of pathogenicity for this variant was not provided in the report (Bode et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 32319239, 24108130) - |
Hereditary hyperekplexia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 442 of the GLRA1 protein (p.Arg442His). This variant is present in population databases (rs200130685, gnomAD 0.06%). This missense change has been observed in individual(s) with hyperplexia (PMID: 24108130). This variant is also known as Arg414His. ClinVar contains an entry for this variant (Variation ID: 532834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLRA1 protein function. Experimental studies have shown that this missense change does not substantially affect GLRA1 function (PMID: 24108130). 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