NM_000809.4:c.205+2113A>G

Variant names:

• chr4-46990715-T-C
• rs16859826
• NM_000809.4:c.205+2113A>G

Variant summary

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

The NM_000809.4(GABRA4):​c.205+2113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,220 control chromosomes in the GnomAD database, including 937 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 0.11 (937 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 1 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]

GABRA4 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Illumina

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.179 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.205+2113A>G		intron	N/A	NP_000800.2
	GABRA4	NM_001204266.2		c.148+2113A>G		intron	N/A	NP_001191195.1
	GABRA4	NM_001204267.2		c.148+2113A>G		intron	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.205+2113A>G		intron	N/A	ENSP00000264318.3
	GABRA4	ENST00000502874.1	TSL:5	n.86+2624A>G		intron	N/A	ENSP00000424386.1
	GABRA4	ENST00000508560.5	TSL:3	n.*26+2113A>G		intron	N/A	ENSP00000425445.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16130 AN: 152102 Hom.: 932 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.0977

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0958

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.106 AC: 16146 AN: 152220 Hom.: 937 Cov.: 32 AF XY: 0.107 AC XY: 7991 AN XY: 74432

African (AFR) AF: 0.123 AC: 5123 AN: 41522

American (AMR) AF: 0.0842 AC: 1289 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3472

East Asian (EAS) AF: 0.109 AC: 562 AN: 5174

South Asian (SAS) AF: 0.189 AC: 913 AN: 4820

European-Finnish (FIN) AF: 0.0977 AC: 1036 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0958 AC: 6514 AN: 68010

Other (OTH) AF: 0.101 AC: 214 AN: 2110

Alfa AF: 0.112 Hom.: 125

Bravo AF: 0.102

Asia WGS AF: 0.164 AC: 569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	15
DANN	Benign	0.57
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16859826; hg19: chr4-46992732; COSMIC: COSV51926641; COSMIC: COSV51926641;