rs2280072

Variant names:

• chr4-46993153-G-C
• rs2280072
• NM_000809.4:c.86+186C>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.86+186C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,206 control chromosomes in the GnomAD database, including 940 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 0.11 (940 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.223
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.86+186C>G		intron_variant	Intron 1 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.30-207C>G		intron_variant	Intron 1 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.30-207C>G		intron_variant	Intron 1 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.86+186C>G		intron_variant	Intron 1 of 8	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16194 AN: 152088 Hom.: 935 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0972

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0956

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.106 AC: 16210 AN: 152206 Hom.: 940 Cov.: 32 AF XY: 0.108 AC XY: 8023 AN XY: 74432

African (AFR) AF: 0.125 AC: 5193 AN: 41522

American (AMR) AF: 0.0842 AC: 1288 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3472

East Asian (EAS) AF: 0.110 AC: 567 AN: 5162

South Asian (SAS) AF: 0.191 AC: 920 AN: 4826

European-Finnish (FIN) AF: 0.0972 AC: 1031 AN: 10608

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0956 AC: 6502 AN: 67998

Other (OTH) AF: 0.101 AC: 214 AN: 2110

Alfa AF: 0.112 Hom.: 117

Bravo AF: 0.102

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.7
DANN	Benign	0.39
PhyloP100		-0.22
PromoterAI		0.015	Neutral
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: rs2280072; hg19: chr4-46995170;