rs281864921
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000171.4(GLRA1):c.921del(p.Tyr307Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
GLRA1
NM_000171.4 frameshift
NM_000171.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.482
Genes affected
GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-151829058-CA-C is Pathogenic according to our data. Variant chr5-151829058-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38335.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.921del | p.Tyr307Ter | frameshift_variant | 8/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.921del | p.Tyr307Ter | frameshift_variant | 8/9 | ||
GLRA1 | NM_001292000.2 | c.672del | p.Tyr224Ter | frameshift_variant | 7/8 | ||
GLRA1 | XM_047417105.1 | c.969del | p.Tyr323Ter | frameshift_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.921del | p.Tyr307Ter | frameshift_variant | 8/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.921del | p.Tyr307Ter | frameshift_variant | 8/9 | 1 | A1 | ||
GLRA1 | ENST00000462581.6 | c.*679del | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hyperekplexia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | Oct 04, 2012 | - - |
Hereditary hyperekplexia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2018 | This sequence change creates a premature translational stop signal (p.Tyr307*) in the GLRA1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GLRA1 are known to be pathogenic (PMID: 20631190). This variant has been observed to segregate with hyperekplexia in a family (PMID: 15771552). ClinVar contains an entry for this variant (Variation ID: 38335). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at