NM_000809.4:c.1090G>C

Variant summary

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

The NM_000809.4(GABRA4):​c.1090G>C​(p.Ala364Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A364T) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

GABRA4
NM_000809.4 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.224
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=0.12329084).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GABRA4NM_000809.4 linkc.1090G>C p.Ala364Pro missense_variant Exon 8 of 9 ENST00000264318.4 NP_000800.2 P48169X5D7F5
GABRA4NM_001204266.2 linkc.1033G>C p.Ala345Pro missense_variant Exon 8 of 9 NP_001191195.1 P48169
GABRA4NM_001204267.2 linkc.880G>C p.Ala294Pro missense_variant Exon 7 of 8 NP_001191196.1 P48169

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GABRA4ENST00000264318.4 linkc.1090G>C p.Ala364Pro missense_variant Exon 8 of 9 1 NM_000809.4 ENSP00000264318.3 P48169

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151736
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00000400
AC:
1
AN:
249898
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135072
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459680
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726110
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151736
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74064
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
6.2
DANN
Uncertain
0.97
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.68
T
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
0.55
N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.78
N
REVEL
Benign
0.13
Sift
Benign
0.031
D
Sift4G
Benign
0.12
T
Polyphen
0.068
B
Vest4
0.12
MutPred
0.43
Gain of relative solvent accessibility (P = 0.0166);
MVP
0.58
MPC
0.070
ClinPred
0.079
T
GERP RS
2.1
Varity_R
0.11
gMVP
0.47

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: rs769919150; hg19: chr4-46967031; API