rs17599416

chr4-46971421-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.81).
• 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/exons	MANE	UniProt
GABRA4	NM_000809.4	c.722-186T>C		intron_variant		ENST00000264318.4
GABRA4	NM_001204266.2	c.665-186T>C		intron_variant
GABRA4	NM_001204267.2	c.664+2811T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.722-186T>C		intron_variant		1	NM_000809.4	P1
GABRA4	ENST00000502874.1	c.*492-186T>C		intron_variant, NMD_transcript_variant		5
GABRA4	ENST00000508560.5	c.*543-186T>C		intron_variant, NMD_transcript_variant		3
GABRA4	ENST00000511523.5	c.*542+2811T>C		intron_variant, NMD_transcript_variant		3

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

Gnomad4 AFR AF: 0.0867

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.0585

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.134

Alfa AF: 0.119 Hom.: 277

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17599416; hg19: chr4-46973438;