NM_000809.4:c.1184A>G

Variant names:

• chr4-46928706-T-C
• rs1721327867
• NM_000809.4:c.1184A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_000809.4(GABRA4):​c.1184A>G​(p.His395Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GABRA4 NM_000809.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• Publications: 0 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

ENSG00000299086 (HGNC:58780):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13828096).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	NM_000809.4	MANE Select	c.1184A>G	p.His395Arg	missense	Exon 9 of 9	NP_000800.2
	GABRA4	NM_001204266.2		c.1127A>G	p.His376Arg	missense	Exon 9 of 9	NP_001191195.1
	GABRA4	NM_001204267.2		c.974A>G	p.His325Arg	missense	Exon 8 of 8	NP_001191196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.1184A>G	p.His395Arg	missense	Exon 9 of 9	ENSP00000264318.3	P48169
	GABRA4	ENST00000900310.1		c.1031A>G	p.His344Arg	missense	Exon 8 of 8	ENSP00000570369.1
	GABRA4	ENST00000508560.5	TSL:3	n.*1005A>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000425445.1	D6R924

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460820 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726730

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111360

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.40		Gain of MoRF binding (P = 0.0099)
MVP		0.64
MPC		0.11
ClinPred		0.46	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.34
Mutation Taster		=82/18	polymorphism

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: rs1721327867; hg19: chr4-46930723;