4-46993643-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000809.4(GABRA4):​c.-219C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000024 in 416,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

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.-219C>G		upstream_gene	N/A	NP_000800.2
	GABRA4	NM_001204266.2		c.-208C>G		upstream_gene	N/A	NP_001191195.1
	GABRA4	NM_001204267.2		c.-208C>G		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.-219C>G		upstream_gene	N/A	ENSP00000264318.3
	GABRB1	ENST00000513567.5	TSL:4	c.-303G>C		upstream_gene	N/A	ENSP00000426753.1
	GABRA4	ENST00000502874.1	TSL:5	n.-219C>G		upstream_gene	N/A	ENSP00000424386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000240 AC: 1 AN: 416898 Hom.: 0 Cov.: 3 AF XY: 0.00000453 AC XY: 1 AN XY: 220862

African (AFR) AF: 0.00 AC: 0 AN: 11722

American (AMR) AF: 0.00 AC: 0 AN: 18640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12672

East Asian (EAS) AF: 0.00 AC: 0 AN: 27992

South Asian (SAS) AF: 0.0000216 AC: 1 AN: 46300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1820

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 248458

Other (OTH) AF: 0.00 AC: 0 AN: 23790

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1004

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		1.5
PromoterAI		-0.026	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;