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rs149023945

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000171.4(GLRA1):ā€‹c.117G>Cā€‹(p.Ser39=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,946 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. S39S) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0017 ( 1 hom., cov: 32)
Exomes š‘“: 0.0018 ( 2 hom. )

Consequence

GLRA1
NM_000171.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.44
Variant links:
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 -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-151892378-C-G is Benign according to our data. Variant chr5-151892378-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 352321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-4.44 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00166 (253/152228) while in subpopulation NFE AF= 0.00231 (157/68012). AF 95% confidence interval is 0.00201. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLRA1NM_000171.4 linkuse as main transcriptc.117G>C p.Ser39= synonymous_variant 2/9 ENST00000274576.9
GLRA1NM_001146040.2 linkuse as main transcriptc.117G>C p.Ser39= synonymous_variant 2/9
GLRA1XM_047417105.1 linkuse as main transcriptc.165G>C p.Ser55= synonymous_variant 2/9
GLRA1NM_001292000.2 linkuse as main transcriptc.-65-5590G>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLRA1ENST00000274576.9 linkuse as main transcriptc.117G>C p.Ser39= synonymous_variant 2/91 NM_000171.4 P4P23415-2
GLRA1ENST00000455880.2 linkuse as main transcriptc.117G>C p.Ser39= synonymous_variant 2/91 A1P23415-1
GLRA1ENST00000471351.2 linkuse as main transcriptn.400G>C non_coding_transcript_exon_variant 2/81
GLRA1ENST00000462581.6 linkuse as main transcriptc.57-5590G>C intron_variant, NMD_transcript_variant 1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00165
AC:
251
AN:
152110
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000411
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00424
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00229
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00148
AC:
373
AN:
251252
Hom.:
1
AF XY:
0.00162
AC XY:
220
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00134
Gnomad FIN exome
AF:
0.00444
Gnomad NFE exome
AF:
0.00185
Gnomad OTH exome
AF:
0.00228
GnomAD4 exome
AF:
0.00178
AC:
2601
AN:
1461718
Hom.:
2
Cov.:
31
AF XY:
0.00185
AC XY:
1344
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00139
Gnomad4 FIN exome
AF:
0.00431
Gnomad4 NFE exome
AF:
0.00190
Gnomad4 OTH exome
AF:
0.00167
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00166
AC:
253
AN:
152228
Hom.:
1
Cov.:
32
AF XY:
0.00161
AC XY:
120
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00424
Gnomad4 NFE
AF:
0.00231
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00140
Hom.:
0
Bravo
AF:
0.00117
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00196
EpiControl
AF:
0.00196

ClinVar

Significance: Benign/Likely 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 07, 2021- -
Hereditary hyperekplexia Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.68
DANN
Benign
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149023945; hg19: chr5-151271939; API