5-161847218-A-G

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: 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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_000806.5	c.-441A>G		5_prime_UTR_variant	Exon 1 of 11		NP_000797.2
LOC105377696	XR_941158.4	n.74+3302T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000023897.10	c.-441A>G		5_prime_UTR_variant	Exon 1 of 11	1		ENSP00000023897.6
GABRA1	ENST00000638112.1	c.-496A>G		5_prime_UTR_variant	Exon 1 of 11	5		ENSP00000489839.1
ENSG00000294143	ENST00000721460.1	n.71+3302T>C		intron_variant	Intron 1 of 2

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 = 0.002339), 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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 13 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;