4-46928732-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000809.4(GABRA4):​c.1158G>A​(p.Met386Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA4
NM_000809.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28
Variant links:
Genes affected
GABRA4 (HGNC:4078): (gamma-aminobutyric acid type A receptor subunit alpha4) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1792284).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GABRA4NM_000809.4 linkc.1158G>A p.Met386Ile missense_variant Exon 9 of 9 ENST00000264318.4 NP_000800.2 P48169X5D7F5
GABRA4NM_001204266.2 linkc.1101G>A p.Met367Ile missense_variant Exon 9 of 9 NP_001191195.1 P48169
GABRA4NM_001204267.2 linkc.948G>A p.Met316Ile missense_variant Exon 8 of 8 NP_001191196.1 P48169

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GABRA4ENST00000264318.4 linkc.1158G>A p.Met386Ile missense_variant Exon 9 of 9 1 NM_000809.4 ENSP00000264318.3 P48169

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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
May 17, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
0.0016
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
21
DANN
Benign
0.92
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.20
Eigen_PC
Benign
0.052
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.040
N
REVEL
Benign
0.27
Sift
Benign
0.31
T
Sift4G
Benign
0.56
T
Polyphen
0.0020
B
Vest4
0.20
MutPred
0.48
Loss of MoRF binding (P = 0.1063);
MVP
0.49
MPC
0.069
ClinPred
0.29
T
GERP RS
5.6
Varity_R
0.22
gMVP
0.23

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: chr4-46930749; API