rs17599416

Variant names:

• chr4-46971421-A-G
• rs17599416
• NM_000809.4:c.722-186T>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.722-186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 151,498 control chromosomes in the GnomAD database, including 2,011 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 0.14 (2011 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• Publications: 7 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.722-186T>C		intron_variant	Intron 6 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.665-186T>C		intron_variant	Intron 6 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.664+2811T>C		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.722-186T>C		intron_variant	Intron 6 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000502874.1	n.*492-186T>C		intron_variant	Intron 5 of 5	5		ENSP00000424386.1
GABRA4	ENST00000508560.5	n.*543-186T>C		intron_variant	Intron 6 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5	n.*542+2811T>C		intron_variant	Intron 6 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20570 AN: 151380 Hom.: 1994 Cov.: 32

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.136 AC: 20605 AN: 151498 Hom.: 2011 Cov.: 32 AF XY: 0.144 AC XY: 10680 AN XY: 74046

African (AFR) AF: 0.0867 AC: 3598 AN: 41478

American (AMR) AF: 0.322 AC: 4872 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 202 AN: 3454

East Asian (EAS) AF: 0.277 AC: 1415 AN: 5100

South Asian (SAS) AF: 0.115 AC: 553 AN: 4826

European-Finnish (FIN) AF: 0.222 AC: 2350 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7245 AN: 67616

Other (OTH) AF: 0.134 AC: 281 AN: 2098

Alfa AF: 0.128 Hom.: 517

Bravo AF: 0.147

Asia WGS AF: 0.199 AC: 691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.49
PhyloP100		0.13
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: rs17599416; hg19: chr4-46973438;