4-46965556-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):c.875-327C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 151,492 control chromosomes in the GnomAD database, including 20,915 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 0.52 (20915 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.130

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA4	NM_000809.4	c.875-327C>G		intron_variant		ENST00000264318.4
GABRA4	NM_001204266.2	c.818-327C>G		intron_variant
GABRA4	NM_001204267.2	c.665-327C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.875-327C>G		intron_variant		1	NM_000809.4	P1
GABRA4	ENST00000508560.5	c.*696-327C>G		intron_variant, NMD_transcript_variant		3
GABRA4	ENST00000511523.5	c.*543-327C>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.521 AC: 78900 AN: 151376 Hom.: 20875 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.521 AC: 78993 AN: 151492 Hom.: 20915 Cov.: 32 AF XY: 0.522 AC XY: 38673 AN XY: 74032

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.511

Alfa AF: 0.395 Hom.: 1059

Bravo AF: 0.526

Asia WGS AF: 0.602 AC: 2093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	4.5
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2280073; hg19: chr4-46967573;