5-151822686-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000171.4(GLRA1):c.1337T>C(p.Val446Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V446I) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.1337T>C | p.Val446Ala | missense_variant | 9/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.1361T>C | p.Val454Ala | missense_variant | 9/9 | ||
GLRA1 | NM_001292000.2 | c.1088T>C | p.Val363Ala | missense_variant | 8/8 | ||
GLRA1 | XM_047417105.1 | c.1385T>C | p.Val462Ala | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.1337T>C | p.Val446Ala | missense_variant | 9/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.1361T>C | p.Val454Ala | missense_variant | 9/9 | 1 | A1 | ||
GLRA1 | ENST00000462581.6 | c.*1095T>C | 3_prime_UTR_variant, NMD_transcript_variant | 8/8 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135794
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460178Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726570
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
Hereditary hyperekplexia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 446 of the GLRA1 protein (p.Val446Ala). This variant is present in population databases (rs774573940, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with GLRA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1958927). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GLRA1 protein function with a negative predictive value of 95%. 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