Genetic Variant GABRA4:c.87-12_87-10dupTTT (chr4-46992955-G-GAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000809.4(GABRA4):c.87-12_87-10dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

GABRA4
NM_000809.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0260

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4 link	c.87-12_87-10dupTTT	intron_variant	Intron 1 of 8	ENST00000264318.4	NP_000800.2	P48169X5D7F5
GABRA4	NM_001204266.2 link	c.30-12_30-10dupTTT	intron_variant	Intron 1 of 8		NP_001191195.1	P48169
GABRA4	NM_001204267.2 link	c.30-12_30-10dupTTT	intron_variant	Intron 1 of 7		NP_001191196.1	P48169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4 link	c.87-12_87-10dupTTT		intron_variant	Intron 1 of 8	1	NM_000809.4	ENSP00000264318.3		P48169

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

144084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000206

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000407

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000234

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000342

AC:

AN:

172330

AF XY:

0.000352

show subpopulations

Gnomad AFR exome

AF:

0.000542

Gnomad AMR exome

AF:

0.000279

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000911

Gnomad FIN exome

AF:

0.000281

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

AF:

0.000438

AC:

506

AN:

1155902

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

243

AN XY:

584678

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000866

AC:

AN:

26560

American (AMR)

AF:

0.000434

AC:

AN:

36830

Ashkenazi Jewish (ASJ)

AF:

0.000221

AC:

AN:

22596

East Asian (EAS)

AF:

0.000473

AC:

AN:

35954

South Asian (SAS)

AF:

0.000228

AC:

AN:

74584

European-Finnish (FIN)

AF:

0.000127

AC:

AN:

47148

Middle Eastern (MID)

AF:

0.000832

AC:

AN:

4808

European-Non Finnish (NFE)

AF:

0.000467

AC:

401

AN:

858102

Other (OTH)

AF:

0.000345

AC:

AN:

49320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000146

AC:

AN:

144140

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

69730

show subpopulations

African (AFR)

AF:

0.000306

AC:

AN:

39194

American (AMR)

AF:

0.000206

AC:

AN:

14572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.000409

AC:

AN:

4894

South Asian (SAS)

AF:

0.00

AC:

AN:

4464

European-Finnish (FIN)

AF:

0.000234

AC:

AN:

8530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65926

Other (OTH)

AF:

0.000501

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00112

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.026

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-46992955-GAAAA-GAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over