Genetic Variant GABRA4:c.875-804A>G (chr4-46966033-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000809.4(GABRA4):c.875-804A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 150,086 control chromosomes in the GnomAD database, including 4,345 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4345 hom., cov: 32)

Consequence

GABRA4
NM_000809.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0510

Publications

21 publications found

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]

GABRA4 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Illumina

GABRA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GABRA4	NM_000809.4 link	c.875-804A>G	intron_variant	Intron 7 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2 link	c.818-804A>G	intron_variant	Intron 7 of 8		NP_001191195.1
GABRA4	NM_001204267.2 link	c.665-804A>G	intron_variant	Intron 6 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GABRA4	ENST00000264318.4 link	c.875-804A>G	intron_variant	Intron 7 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000508560.5 link	n.*696-804A>G	intron_variant	Intron 7 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5 link	n.*543-804A>G	intron_variant	Intron 6 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35377

AN:

149964

Hom.:

4345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.274

Gnomad EAS

AF:

0.322

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.250

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.236

AC:

35390

AN:

150086

Hom.:

4345

Cov.:

AF XY:

0.228

AC XY:

16731

AN XY:

73382

show subpopulations

African (AFR)

AF:

0.196

AC:

8108

AN:

41328

American (AMR)

AF:

0.197

AC:

2964

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

935

AN:

3410

East Asian (EAS)

AF:

0.320

AC:

1633

AN:

5098

South Asian (SAS)

AF:

0.173

AC:

831

AN:

4814

European-Finnish (FIN)

AF:

0.157

AC:

1652

AN:

10504

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.277

AC:

18491

AN:

66638

Other (OTH)

AF:

0.248

AC:

515

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1357

2714

4071

5428

6785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.250

Hom.:

4266

Bravo

AF:

0.235

Asia WGS

AF:

0.212

AC:

734

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

6.7

(source)

DANN

Benign

0.62

PhyloP100

0.051

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over