4-46950454-A-G

Variant names:

• chr4-46950454-A-G
• rs1512130
• NM_000809.4:c.1134+14516T>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.1134+14516T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,746 control chromosomes in the GnomAD database, including 31,890 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 0.64 (31890 hom., cov: 31)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000809.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	NM_000809.4	MANE Select	c.1134+14516T>C		intron	N/A	NP_000800.2
	GABRA4	NM_001204266.2		c.1077+14516T>C		intron	N/A	NP_001191195.1
	GABRA4	NM_001204267.2		c.924+14516T>C		intron	N/A	NP_001191196.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.1134+14516T>C		intron	N/A	ENSP00000264318.3
	GABRA4	ENST00000508560.5	TSL:3	n.*955+14516T>C		intron	N/A	ENSP00000425445.1
	GABRA4	ENST00000511523.5	TSL:3	n.*802+14516T>C		intron	N/A	ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97727 AN: 151628 Hom.: 31856 Cov.: 31

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.645 AC: 97817 AN: 151746 Hom.: 31890 Cov.: 31 AF XY: 0.649 AC XY: 48084 AN XY: 74134

African (AFR) AF: 0.535 AC: 22129 AN: 41358

American (AMR) AF: 0.700 AC: 10627 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2207 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3906 AN: 5144

South Asian (SAS) AF: 0.728 AC: 3504 AN: 4816

European-Finnish (FIN) AF: 0.720 AC: 7580 AN: 10528

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45783 AN: 67942

Other (OTH) AF: 0.637 AC: 1336 AN: 2096

Alfa AF: 0.662 Hom.: 115683

Bravo AF: 0.637

Asia WGS AF: 0.741 AC: 2574 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.37
PhyloP100		0.010
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: rs1512130; hg19: chr4-46952471;