NM_001127644.2:c.187+3553A>G

Variant names:

• chr5-161857823-A-G
• rs4263535
• NM_001127644.2:c.187+3553A>G

Variant summary

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

The NM_001127644.2(GABRA1):​c.187+3553A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 151,380 control chromosomes in the GnomAD database, including 7,596 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 0.28 (7596 hom., cov: 31)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.736
• Publications: 14 publications found

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127644.2. 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
	GABRA1	NM_001127644.2	MANE Select	c.187+3553A>G		intron	N/A	NP_001121116.1
	GABRA1	NM_000806.5		c.187+3553A>G		intron	N/A	NP_000797.2
	GABRA1	NM_001127643.2		c.187+3553A>G		intron	N/A	NP_001121115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.187+3553A>G		intron	N/A	ENSP00000377517.4
	GABRA1	ENST00000023897.10	TSL:1	c.187+3553A>G		intron	N/A	ENSP00000023897.6
	GABRA1	ENST00000428797.7	TSL:1	c.187+3553A>G		intron	N/A	ENSP00000393097.2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42141 AN: 151262 Hom.: 7578 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.259

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

GnomAD4 genome AF: 0.279 AC: 42183 AN: 151380 Hom.: 7596 Cov.: 31 AF XY: 0.279 AC XY: 20614 AN XY: 73964

African (AFR) AF: 0.495 AC: 20480 AN: 41350

American (AMR) AF: 0.187 AC: 2839 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 754 AN: 3450

East Asian (EAS) AF: 0.447 AC: 2304 AN: 5150

South Asian (SAS) AF: 0.350 AC: 1688 AN: 4816

European-Finnish (FIN) AF: 0.162 AC: 1713 AN: 10568

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11684 AN: 67578

Other (OTH) AF: 0.262 AC: 550 AN: 2100

Alfa AF: 0.194 Hom.: 5094

Bravo AF: 0.293

Asia WGS AF: 0.429 AC: 1491 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.27
DANN	Benign	0.44
PhyloP100		-0.74
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: rs4263535; hg19: chr5-161284829;