rs9291296

Positions:

• chr4-46920933-A-G
• chr4-46920933-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.*7292T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 151,718 control chromosomes in the GnomAD database, including 4,582 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 (4582 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GABRA4 NM_000809.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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=-0.9).
• 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.*7292T>C		3_prime_UTR_variant	9/9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.*7292T>C		3_prime_UTR_variant	9/9		NP_001191195.1
GABRA4	NM_001204267.2	c.*7292T>C		3_prime_UTR_variant	8/8		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318	c.*7292T>C		3_prime_UTR_variant	9/9	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36393 AN: 151602 Hom.: 4584 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.248

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.240 AC: 36402 AN: 151718 Hom.: 4582 Cov.: 32 AF XY: 0.232 AC XY: 17216 AN XY: 74142

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.246

Alfa AF: 0.276 Hom.: 4861

Bravo AF: 0.240

Asia WGS AF: 0.205 AC: 705 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs9291296; hg19: chr4-46922950;