rs13151769

Variant names:

• chr4-46993643-G-A
• rs13151769
• NM_000809.4:c.-219C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-46993643-G-A
• chr4-46993643-G-C

Variant summary

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

The NM_000809.4(GABRA4):​c.-219C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 568,026 control chromosomes in the GnomAD database, including 32,087 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 (8743 hom., cov: 32)
  • Exomes 𝑓: 0.33 (23344 hom.)
• Consequence: GABRA4 NM_000809.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• 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]

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=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.-219C>T		upstream_gene_variant		ENST00000264318.4	NP_000800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.-219C>T		upstream_gene_variant		1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50891 AN: 151772 Hom.: 8720 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.346

GnomAD4 exome AF: 0.329 AC: 136933 AN: 416136 Hom.: 23344 Cov.: 3 AF XY: 0.322 AC XY: 71075 AN XY: 220470

African (AFR) AF: 0.347 AC: 4055 AN: 11694

American (AMR) AF: 0.304 AC: 5666 AN: 18614

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 4891 AN: 12634

East Asian (EAS) AF: 0.323 AC: 9023 AN: 27938

South Asian (SAS) AF: 0.213 AC: 9853 AN: 46298

European-Finnish (FIN) AF: 0.234 AC: 5956 AN: 25450

Middle Eastern (MID) AF: 0.379 AC: 687 AN: 1814

European-Non Finnish (NFE) AF: 0.358 AC: 88723 AN: 247956

Other (OTH) AF: 0.340 AC: 8079 AN: 23738

GnomAD4 genome AF: 0.335 AC: 50957 AN: 151890 Hom.: 8743 Cov.: 32 AF XY: 0.324 AC XY: 24040 AN XY: 74206

African (AFR) AF: 0.341 AC: 14128 AN: 41424

American (AMR) AF: 0.338 AC: 5157 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1345 AN: 3472

East Asian (EAS) AF: 0.339 AC: 1741 AN: 5134

South Asian (SAS) AF: 0.206 AC: 992 AN: 4822

European-Finnish (FIN) AF: 0.198 AC: 2100 AN: 10580

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24364 AN: 67870

Other (OTH) AF: 0.348 AC: 736 AN: 2112

Alfa AF: 0.319 Hom.: 1004

Bravo AF: 0.350

Asia WGS AF: 0.267 AC: 929 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		1.5
PromoterAI		-0.021	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13151769; hg19: chr4-46995660;