rs760390019
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate
The NM_000171.4(GLRA1):c.292G>A(p.Asp98Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,876 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 Pathogenic (★).
Frequency
Consequence
NM_000171.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.292G>A | p.Asp98Asn | missense_variant | Exon 4 of 9 | ENST00000274576.9 | NP_000162.2 | |
GLRA1 | NM_001146040.2 | c.292G>A | p.Asp98Asn | missense_variant | Exon 4 of 9 | NP_001139512.1 | ||
GLRA1 | NM_001292000.2 | c.43G>A | p.Asp15Asn | missense_variant | Exon 3 of 8 | NP_001278929.1 | ||
GLRA1 | XM_047417105.1 | c.340G>A | p.Asp114Asn | missense_variant | Exon 4 of 9 | XP_047273061.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251420Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727192
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74292
ClinVar
Submissions by phenotype
Hereditary hyperekplexia Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 98 of the GLRA1 protein (p.Asp98Asn). This variant is present in population databases (rs760390019, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 25568133, 32332682). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as D70N. ClinVar contains an entry for this variant (Variation ID: 464186). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLRA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 25568133). This variant disrupts the p.Asp98 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30866851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at