rs1512136

Positions:

• chr4-46930189-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.1135-1434A>G		intron_variant		ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.1078-1434A>G		intron_variant			NP_001191195.1
GABRA4	NM_001204267.2	c.925-1434A>G		intron_variant			NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.1135-1434A>G		intron_variant		1	NM_000809.4	ENSP00000264318	P1
GABRA4	ENST00000508560.5	c.*956-1434A>G		intron_variant, NMD_transcript_variant		3		ENSP00000425445
GABRA4	ENST00000511523.5	c.*803-1434A>G		intron_variant, NMD_transcript_variant		3		ENSP00000422152

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

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.247

Alfa AF: 0.266 Hom.: 2567

Bravo AF: 0.244

Asia WGS AF: 0.206 AC: 714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0090
DANN	Benign	0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1512136; hg19: chr4-46932206;