chr4-46920933-A-G

Variant names:

• chr4-46920933-A-G
• rs9291296
• NM_000809.4:c.*7292T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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

ENSG00000299086 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.*7292T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.*7292T>C		3_prime_UTR_variant	Exon 9 of 9		NP_001191195.1
GABRA4	NM_001204267.2	c.*7292T>C		3_prime_UTR_variant	Exon 8 of 8		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.*7292T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000809.4	ENSP00000264318.3
ENSG00000299086	ENST00000760386.1	n.173-7511A>G		intron_variant	Intron 1 of 1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.197 AC: 8178 AN: 41448

American (AMR) AF: 0.194 AC: 2954 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 942 AN: 3466

East Asian (EAS) AF: 0.287 AC: 1485 AN: 5170

South Asian (SAS) AF: 0.185 AC: 891 AN: 4816

European-Finnish (FIN) AF: 0.170 AC: 1794 AN: 10574

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19249 AN: 67706

Other (OTH) AF: 0.246 AC: 518 AN: 2106

Alfa AF: 0.273 Hom.: 5625

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
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9291296; hg19: chr4-46922950;