rs11576001

Variant names:

• chr5-161847218-A-G
• rs11576001
• ENST00000023897.10:c.-441A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000806.5(GABRA1):​c.-441A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 151,258 control chromosomes in the GnomAD database, including 7,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7786 hom., cov: 30)
  • Exomes 𝑓: 0.20 (0 hom.)
• Consequence: GABRA1 NM_000806.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.768
• Publications: 7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  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

ENSG00000294143 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-161847218-A-G is Benign according to our data. Variant chr5-161847218-A-G is described in ClinVar as Benign. ClinVar VariationId is 352585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000806.5. 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
	GABRA1	NM_000806.5		c.-441A>G		5_prime_UTR	Exon 1 of 11	NP_000797.2	A8K177

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000023897.10	TSL:1	c.-441A>G		5_prime_UTR	Exon 1 of 11	ENSP00000023897.6	P14867
	GABRA1	ENST00000638112.1	TSL:5	c.-496A>G		5_prime_UTR	Exon 1 of 11	ENSP00000489839.1	P14867
	ENSG00000294143	ENST00000721460.1		n.71+3302T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45049 AN: 151130 Hom.: 7771 Cov.: 30

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.287

GnomAD4 exome AF: 0.200 AC: 2 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 2 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.298 AC: 45095 AN: 151248 Hom.: 7786 Cov.: 30 AF XY: 0.300 AC XY: 22173 AN XY: 73850

African (AFR) AF: 0.470 AC: 19323 AN: 41156

American (AMR) AF: 0.240 AC: 3643 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 809 AN: 3468

East Asian (EAS) AF: 0.388 AC: 1979 AN: 5098

South Asian (SAS) AF: 0.411 AC: 1926 AN: 4690

European-Finnish (FIN) AF: 0.198 AC: 2077 AN: 10510

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14518 AN: 67826

Other (OTH) AF: 0.292 AC: 615 AN: 2106

Alfa AF: 0.241 Hom.: 5747

Bravo AF: 0.309

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, idiopathic generalized, susceptibility to, 13 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.054
DANN	Benign	0.32
PhyloP100		-0.77
PromoterAI		0.0058	Neutral
Mutation Taster		=300/0	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: rs11576001; hg19: chr5-161274224; COSMIC: COSV50115094; COSMIC: COSV50115094;