4-46926817-C-T

Position:

• chr4-46926817-C-T

Variant summary

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

The NM_000809.4(GABRA4):​c.*1408G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 151,672 control chromosomes in the GnomAD database, including 5,039 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 0.25 (5039 hom., cov: 31)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: GABRA4 NM_000809.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926

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.*1408G>A		3_prime_UTR_variant	9/9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.*1408G>A		3_prime_UTR_variant	9/9		NP_001191195.1
GABRA4	NM_001204267.2	c.*1408G>A		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.*1408G>A		3_prime_UTR_variant	9/9	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38551 AN: 151548 Hom.: 5034 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.254 AC: 38580 AN: 151668 Hom.: 5039 Cov.: 31 AF XY: 0.246 AC XY: 18257 AN XY: 74136

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.256

Alfa AF: 0.213 Hom.: 811

Bravo AF: 0.256

Asia WGS AF: 0.212 AC: 736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.32

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: rs17599102; hg19: chr4-46928834;