rs281864913
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5
The NM_000171.4(GLRA1):c.1030C>T(p.Arg344*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,018 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000171.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.1030C>T | p.Arg344* | stop_gained | 8/9 | ENST00000274576.9 | NP_000162.2 | |
GLRA1 | NM_001146040.2 | c.1030C>T | p.Arg344* | stop_gained | 8/9 | NP_001139512.1 | ||
GLRA1 | NM_001292000.2 | c.781C>T | p.Arg261* | stop_gained | 7/8 | NP_001278929.1 | ||
GLRA1 | XM_047417105.1 | c.1078C>T | p.Arg360* | stop_gained | 8/9 | XP_047273061.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.1030C>T | p.Arg344* | stop_gained | 8/9 | 1 | NM_000171.4 | ENSP00000274576.5 | ||
GLRA1 | ENST00000455880.2 | c.1030C>T | p.Arg344* | stop_gained | 8/9 | 1 | ENSP00000411593.2 | |||
GLRA1 | ENST00000462581.6 | n.*788C>T | non_coding_transcript_exon_variant | 7/8 | 1 | ENSP00000430595.1 | ||||
GLRA1 | ENST00000462581.6 | n.*788C>T | 3_prime_UTR_variant | 7/8 | 1 | ENSP00000430595.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251076Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135678
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461730Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727154
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74468
ClinVar
Submissions by phenotype
Hereditary hyperekplexia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Arg344*) in the GLRA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the GLRA1 protein. This variant is present in population databases (rs281864913, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hyperekplexia (PMID: 15365143). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242682). This variant disrupts the p.Arg420 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10514101, 12169101, 19732286, 20631190, 25036534). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2021 | Identified in patients with hyperekplexia who harbored a second GLRA1 variant on the opposite allele (in trans) in published literature (Zhang et al., 2020; Tsai et al., 2004); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 106 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 25036534, 10514101, 20631190, 25525159, 19732286, 12169101, 15365143, 32332682, 17641268) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at