NM_000809.4:c.1134+13106C>G

Variant names:

• chr4-46951864-G-C
• rs1912960
• NM_000809.4:c.1134+13106C>G

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+13106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 151,188 control chromosomes in the GnomAD database, including 6,427 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 0.28 (6427 hom., cov: 30)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.1134+13106C>G		intron_variant	Intron 8 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.1077+13106C>G		intron_variant	Intron 8 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.924+13106C>G		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.1134+13106C>G		intron_variant	Intron 8 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000508560.5	n.*955+13106C>G		intron_variant	Intron 8 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5	n.*802+13106C>G		intron_variant	Intron 7 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42340 AN: 151072 Hom.: 6397 Cov.: 30

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.259

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

GnomAD4 genome AF: 0.281 AC: 42411 AN: 151188 Hom.: 6427 Cov.: 30 AF XY: 0.289 AC XY: 21319 AN XY: 73800

African (AFR) AF: 0.264 AC: 10886 AN: 41180

American (AMR) AF: 0.409 AC: 6176 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3466

East Asian (EAS) AF: 0.373 AC: 1911 AN: 5130

South Asian (SAS) AF: 0.362 AC: 1736 AN: 4798

European-Finnish (FIN) AF: 0.378 AC: 3944 AN: 10438

Middle Eastern (MID) AF: 0.207 AC: 60 AN: 290

European-Non Finnish (NFE) AF: 0.242 AC: 16379 AN: 67758

Other (OTH) AF: 0.260 AC: 547 AN: 2102

Alfa AF: 0.275 Hom.: 786

Bravo AF: 0.283

Asia WGS AF: 0.383 AC: 1328 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.58
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: rs1912960; hg19: chr4-46953881;