rs17599165

Variant names:

• chr4-46938198-T-A
• rs17599165
• NM_000809.4:c.1135-9443A>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.1135-9443A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,096 control chromosomes in the GnomAD database, including 1,675 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 0.12 (1675 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• Publications: 5 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.1135-9443A>T		intron_variant	Intron 8 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.1078-9443A>T		intron_variant	Intron 8 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.925-9443A>T		intron_variant	Intron 7 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.1135-9443A>T		intron_variant	Intron 8 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000508560.5	n.*956-9443A>T		intron_variant	Intron 8 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5	n.*803-9443A>T		intron_variant	Intron 7 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18581 AN: 151978 Hom.: 1667 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.118

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.122 AC: 18610 AN: 152096 Hom.: 1675 Cov.: 32 AF XY: 0.131 AC XY: 9717 AN XY: 74354

African (AFR) AF: 0.0636 AC: 2641 AN: 41546

American (AMR) AF: 0.277 AC: 4219 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1570 AN: 5170

South Asian (SAS) AF: 0.109 AC: 525 AN: 4818

European-Finnish (FIN) AF: 0.220 AC: 2322 AN: 10578

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6843 AN: 67944

Other (OTH) AF: 0.117 AC: 247 AN: 2114

Alfa AF: 0.112 Hom.: 152

Bravo AF: 0.128

Asia WGS AF: 0.203 AC: 705 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.89
DANN	Benign	0.49
PhyloP100		-0.12
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: rs17599165; hg19: chr4-46940215;