NM_000809.4:c.1135-1434A>G

Variant names:

• chr4-46930189-T-C
• rs1512136
• NM_000809.4:c.1135-1434A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.1135-1434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 151,852 control chromosomes in the GnomAD database, including 4,698 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 (4698 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.30
• Publications: 6 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000809.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	NM_000809.4	MANE Select	c.1135-1434A>G		intron	N/A	NP_000800.2
	GABRA4	NM_001204266.2		c.1078-1434A>G		intron	N/A	NP_001191195.1
	GABRA4	NM_001204267.2		c.925-1434A>G		intron	N/A	NP_001191196.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.1135-1434A>G		intron	N/A	ENSP00000264318.3
	GABRA4	ENST00000508560.5	TSL:3	n.*956-1434A>G		intron	N/A	ENSP00000425445.1
	GABRA4	ENST00000511523.5	TSL:3	n.*803-1434A>G		intron	N/A	ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36927 AN: 151734 Hom.: 4700 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.243 AC: 36939 AN: 151852 Hom.: 4698 Cov.: 32 AF XY: 0.235 AC XY: 17475 AN XY: 74214

African (AFR) AF: 0.208 AC: 8625 AN: 41450

American (AMR) AF: 0.196 AC: 2976 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3468

East Asian (EAS) AF: 0.288 AC: 1474 AN: 5126

South Asian (SAS) AF: 0.185 AC: 892 AN: 4820

European-Finnish (FIN) AF: 0.170 AC: 1801 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 78 AN: 290

European-Non Finnish (NFE) AF: 0.285 AC: 19315 AN: 67888

Other (OTH) AF: 0.247 AC: 520 AN: 2104

Alfa AF: 0.267 Hom.: 2897

Bravo AF: 0.244

Asia WGS AF: 0.206 AC: 714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0090
DANN	Benign	0.26
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1512136; hg19: chr4-46932206;