4-46993636-G-T

Variant names:

• chr4-46993636-G-T
• rs13151759
• NM_000809.4:c.-212C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.-212C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 574,154 control chromosomes in the GnomAD database, including 32,591 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 0.34 (8769 hom., cov: 32)
  • Exomes 𝑓: 0.33 (23822 hom.)
• Consequence: GABRA4 NM_000809.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• 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]

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

GABRB1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 45

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.356 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.-212C>A		upstream_gene	N/A	NP_000800.2
	GABRA4	NM_001204266.2		c.-201C>A		upstream_gene	N/A	NP_001191195.1
	GABRA4	NM_001204267.2		c.-201C>A		upstream_gene	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.-212C>A		upstream_gene	N/A	ENSP00000264318.3
	GABRB1	ENST00000513567.5	TSL:4	c.-310G>T		upstream_gene	N/A	ENSP00000426753.1
	GABRA4	ENST00000502874.1	TSL:5	n.-212C>A		upstream_gene	N/A	ENSP00000424386.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50969 AN: 151730 Hom.: 8746 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.330 AC: 139379 AN: 422306 Hom.: 23822 Cov.: 4 AF XY: 0.324 AC XY: 72419 AN XY: 223734

African (AFR) AF: 0.346 AC: 4092 AN: 11820

American (AMR) AF: 0.304 AC: 5734 AN: 18834

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 4997 AN: 12778

East Asian (EAS) AF: 0.324 AC: 9210 AN: 28446

South Asian (SAS) AF: 0.214 AC: 9908 AN: 46390

European-Finnish (FIN) AF: 0.234 AC: 6148 AN: 26240

Middle Eastern (MID) AF: 0.383 AC: 710 AN: 1856

European-Non Finnish (NFE) AF: 0.359 AC: 90364 AN: 251854

Other (OTH) AF: 0.341 AC: 8216 AN: 24088

GnomAD4 genome AF: 0.336 AC: 51036 AN: 151848 Hom.: 8769 Cov.: 32 AF XY: 0.325 AC XY: 24087 AN XY: 74196

African (AFR) AF: 0.342 AC: 14150 AN: 41416

American (AMR) AF: 0.338 AC: 5169 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3468

East Asian (EAS) AF: 0.340 AC: 1746 AN: 5132

South Asian (SAS) AF: 0.207 AC: 997 AN: 4826

European-Finnish (FIN) AF: 0.199 AC: 2101 AN: 10568

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24384 AN: 67858

Other (OTH) AF: 0.351 AC: 740 AN: 2106

Alfa AF: 0.355 Hom.: 25350

Bravo AF: 0.351

Asia WGS AF: 0.268 AC: 930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		2.1
PromoterAI		-0.027	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13151759; hg19: chr4-46995653;