rs6447517

Positions:

• chr4-46926729-A-T

Variant summary

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

The ENST00000264318.4(GABRA4):​c.*1496T>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 0.377 in 151,622 control chromosomes in the GnomAD database, including 11,082 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 0.38 (11082 hom., cov: 31)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: GABRA4 ENST00000264318.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.*1496T>A		3_prime_UTR_variant	9/9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.*1496T>A		3_prime_UTR_variant	9/9		NP_001191195.1
GABRA4	NM_001204267.2	c.*1496T>A		3_prime_UTR_variant	8/8		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.*1496T>A		3_prime_UTR_variant	9/9	1	NM_000809.4	ENSP00000264318	P1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57102 AN: 151496 Hom.: 11077 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.377 AC: 57134 AN: 151614 Hom.: 11082 Cov.: 31 AF XY: 0.369 AC XY: 27344 AN XY: 74090

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.371

Alfa AF: 0.407 Hom.: 1632

Bravo AF: 0.367

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.42

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: rs6447517; hg19: chr4-46928746;