rs2055943

Variant names:

• chr4-46965262-C-A
• rs2055943
• NM_000809.4:c.875-33G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.875-33G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,369,300 control chromosomes in the GnomAD database, including 49,018 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 0.23 (4358 hom., cov: 32)
  • Exomes 𝑓: 0.27 (44660 hom.)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.875-33G>T		intron_variant	Intron 7 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.818-33G>T		intron_variant	Intron 7 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.665-33G>T		intron_variant	Intron 6 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.875-33G>T		intron_variant	Intron 7 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000508560.5	n.*696-33G>T		intron_variant	Intron 7 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5	n.*543-33G>T		intron_variant	Intron 6 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35414 AN: 151416 Hom.: 4357 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.238 AC: 32519 AN: 136656 AF XY: 0.241

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.267 AC: 324748 AN: 1217766 Hom.: 44660 Cov.: 28 AF XY: 0.265 AC XY: 156051 AN XY: 589614

African (AFR) AF: 0.198 AC: 5146 AN: 26020

American (AMR) AF: 0.135 AC: 2814 AN: 20848

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 4602 AN: 16876

East Asian (EAS) AF: 0.311 AC: 10081 AN: 32440

South Asian (SAS) AF: 0.168 AC: 6890 AN: 40944

European-Finnish (FIN) AF: 0.181 AC: 7994 AN: 44064

Middle Eastern (MID) AF: 0.280 AC: 1347 AN: 4812

European-Non Finnish (NFE) AF: 0.278 AC: 273188 AN: 982802

Other (OTH) AF: 0.259 AC: 12686 AN: 48960

GnomAD4 genome AF: 0.234 AC: 35427 AN: 151534 Hom.: 4358 Cov.: 32 AF XY: 0.226 AC XY: 16744 AN XY: 73986

African (AFR) AF: 0.197 AC: 8168 AN: 41384

American (AMR) AF: 0.196 AC: 2969 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 934 AN: 3462

East Asian (EAS) AF: 0.322 AC: 1643 AN: 5102

South Asian (SAS) AF: 0.173 AC: 830 AN: 4810

European-Finnish (FIN) AF: 0.157 AC: 1656 AN: 10564

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.272 AC: 18451 AN: 67730

Other (OTH) AF: 0.246 AC: 516 AN: 2100

Alfa AF: 0.259 Hom.: 7165

Bravo AF: 0.235

Asia WGS AF: 0.213 AC: 739 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.35
DANN	Benign	0.41
PhyloP100		-0.61
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: rs2055943; hg19: chr4-46967279; COSMIC: COSV51928439;