chr4-47031709-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000812.4(GABRB1):ā€‹c.58A>Gā€‹(p.Thr20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GABRB1
NM_000812.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57
Variant links:
Genes affected
GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.052446842).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRB1NM_000812.4 linkuse as main transcriptc.58A>G p.Thr20Ala missense_variant 1/9 ENST00000295454.8 NP_000803.2
GABRB1XM_017007986.3 linkuse as main transcriptc.58A>G p.Thr20Ala missense_variant 1/5 XP_016863475.1
GABRB1XM_024453976.2 linkuse as main transcriptc.-19-205A>G intron_variant XP_024309744.1
GABRB1XM_024453977.2 linkuse as main transcriptc.-19-205A>G intron_variant XP_024309745.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRB1ENST00000295454.8 linkuse as main transcriptc.58A>G p.Thr20Ala missense_variant 1/91 NM_000812.4 ENSP00000295454 P1P18505-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460898
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726864
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 20 of the GABRB1 protein (p.Thr20Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABRB1-related conditions. 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 GABRB1 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
0.050
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
18
DANN
Benign
0.73
DEOGEN2
Benign
0.016
T
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.64
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.61
T
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.052
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-1.0
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
0.58
N
REVEL
Benign
0.19
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.11
MutPred
0.42
Gain of catalytic residue at T20 (P = 0.3494);
MVP
0.17
MPC
0.016
ClinPred
0.049
T
GERP RS
3.6
Varity_R
0.042
gMVP
0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-47033726; API