rs17112272
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000171.4(GLRA1):c.993C>T(p.Ala331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,614,070 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 5 hom. )
Consequence
GLRA1
NM_000171.4 synonymous
NM_000171.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.942
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 Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
?
Variant 5-151828987-G-A is Benign according to our data. Variant chr5-151828987-G-A is described in ClinVar as [Benign]. Clinvar id is 352311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.942 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00435 (662/152266) while in subpopulation AFR AF= 0.0147 (612/41552). AF 95% confidence interval is 0.0138. There are 6 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 6 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.993C>T | p.Ala331= | synonymous_variant | 8/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.993C>T | p.Ala331= | synonymous_variant | 8/9 | ||
GLRA1 | NM_001292000.2 | c.744C>T | p.Ala248= | synonymous_variant | 7/8 | ||
GLRA1 | XM_047417105.1 | c.1041C>T | p.Ala347= | synonymous_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.993C>T | p.Ala331= | synonymous_variant | 8/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.993C>T | p.Ala331= | synonymous_variant | 8/9 | 1 | A1 | ||
GLRA1 | ENST00000462581.6 | c.*751C>T | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00433 AC: 659AN: 152148Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00111 AC: 279AN: 251038Hom.: 1 AF XY: 0.000789 AC XY: 107AN XY: 135670
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GnomAD4 exome AF: 0.000432 AC: 631AN: 1461804Hom.: 5 Cov.: 31 AF XY: 0.000359 AC XY: 261AN XY: 727204
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GnomAD4 genome ? AF: 0.00435 AC: 662AN: 152266Hom.: 6 Cov.: 32 AF XY: 0.00428 AC XY: 319AN XY: 74468
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyperekplexia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 13, 2019 | - - |
Hereditary hyperekplexia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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