4-46971871-T-C

Position:

• chr4-46971871-T-C

Variant summary

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

The NM_000809.4(GABRA4):​c.722-636A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 151,354 control chromosomes in the GnomAD database, including 1,874 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 0.13 (1874 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.722-636A>G		intron_variant		ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.665-636A>G		intron_variant			NP_001191195.1
GABRA4	NM_001204267.2	c.664+2361A>G		intron_variant			NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.722-636A>G		intron_variant		1	NM_000809.4	ENSP00000264318	P1
GABRA4	ENST00000502874.1	c.*492-636A>G		intron_variant, NMD_transcript_variant		5		ENSP00000424386
GABRA4	ENST00000508560.5	c.*543-636A>G		intron_variant, NMD_transcript_variant		3		ENSP00000425445
GABRA4	ENST00000511523.5	c.*542+2361A>G		intron_variant, NMD_transcript_variant		3		ENSP00000422152

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20131 AN: 151238 Hom.: 1859 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.0581

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.134

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

GnomAD4 genome AF: 0.133 AC: 20161 AN: 151354 Hom.: 1874 Cov.: 32 AF XY: 0.141 AC XY: 10436 AN XY: 73950

Gnomad4 AFR AF: 0.0864

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.0581

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.133

Alfa AF: 0.0748 Hom.: 126

Bravo AF: 0.147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.77

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: rs1512135; hg19: chr4-46973888;