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GeneBe

4-46928488-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000809.4(GABRA4):c.1402G>C(p.Ala468Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GABRA4
NM_000809.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.132
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11277443).
BS2
High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GABRA4NM_000809.4 linkuse as main transcriptc.1402G>C p.Ala468Pro missense_variant 9/9 ENST00000264318.4
GABRA4NM_001204266.2 linkuse as main transcriptc.1345G>C p.Ala449Pro missense_variant 9/9
GABRA4NM_001204267.2 linkuse as main transcriptc.1192G>C p.Ala398Pro missense_variant 8/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GABRA4ENST00000264318.4 linkuse as main transcriptc.1402G>C p.Ala468Pro missense_variant 9/91 NM_000809.4 P1
GABRA4ENST00000508560.5 linkuse as main transcriptc.*1223G>C 3_prime_UTR_variant, NMD_transcript_variant 9/93
GABRA4ENST00000511523.5 linkuse as main transcriptc.*1070G>C 3_prime_UTR_variant, NMD_transcript_variant 8/83

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152036
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
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:
0.0000319
AC:
8
AN:
250930
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135616
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
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:
0.0000353
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461436
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727016
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
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:
0.00000720
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152036
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
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:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 22, 2022The c.1402G>C (p.A468P) alteration is located in exon 9 (coding exon 9) of the GABRA4 gene. This alteration results from a G to C substitution at nucleotide position 1402, causing the alanine (A) at amino acid position 468 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.42
Cadd
Benign
6.4
Dann
Uncertain
0.98
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.23
N
REVEL
Benign
0.13
Sift
Uncertain
0.018
D
Sift4G
Benign
0.18
T
Polyphen
0.30
B
Vest4
0.071
MutPred
0.48
Loss of MoRF binding (P = 0.0509);
MVP
0.22
MPC
0.068
ClinPred
0.046
T
GERP RS
1.8
Varity_R
0.084
gMVP
0.45

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: rs752524741; hg19: chr4-46930505; API