chr5-151892407-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000171.4(GLRA1):​c.88C>A​(p.Arg30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,860 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GLRA1
NM_000171.4 missense

Scores

1
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.4212857).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLRA1NM_000171.4 linkc.88C>A p.Arg30Ser missense_variant 2/9 ENST00000274576.9 NP_000162.2 P23415-2
GLRA1NM_001146040.2 linkc.88C>A p.Arg30Ser missense_variant 2/9 NP_001139512.1 P23415-1
GLRA1XM_047417105.1 linkc.136C>A p.Arg46Ser missense_variant 2/9 XP_047273061.1
GLRA1NM_001292000.2 linkc.-65-5619C>A intron_variant NP_001278929.1 Q14C71

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLRA1ENST00000274576.9 linkc.88C>A p.Arg30Ser missense_variant 2/91 NM_000171.4 ENSP00000274576.5 P23415-2
GLRA1ENST00000455880.2 linkc.88C>A p.Arg30Ser missense_variant 2/91 ENSP00000411593.2 P23415-1
GLRA1ENST00000471351.2 linkn.371C>A non_coding_transcript_exon_variant 2/81
GLRA1ENST00000462581.6 linkn.57-5619C>A intron_variant 1 ENSP00000430595.1 E5RJ70

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251054
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461710
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary hyperekplexia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2025This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 30 of the GLRA1 protein (p.Arg30Ser). This variant is present in population databases (rs369873008, gnomAD 0.02%). 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: 573990). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.83
T;T
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.42
T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
0.34
N;N
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.39
N;N
REVEL
Uncertain
0.32
Sift
Benign
0.29
T;T
Sift4G
Benign
0.63
T;T
Polyphen
1.0
D;D
Vest4
0.44
MVP
0.84
MPC
2.2
ClinPred
0.88
D
GERP RS
5.6
Varity_R
0.17
gMVP
0.54

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: rs369873008; hg19: chr5-151271968; API