5-161850893-A-T

Position:

• chr5-161850893-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000393943.10(GABRA1):​c.74+9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,610,000 control chromosomes in the GnomAD database, including 3,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (302 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3249 hom.)
• Consequence: GABRA1 ENST00000393943.10 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-161850893-A-T is Benign according to our data. Variant chr5-161850893-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 129124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.74+9A>T		intron_variant		ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.74+9A>T		intron_variant		1	NM_001127644.2	ENSP00000377517	P1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8399 AN: 152092 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.0681

GnomAD3 exomes AF: 0.0741 AC: 18605 AN: 251036 Hom.: 841 AF XY: 0.0756 AC XY: 10265 AN XY: 135702

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.0999

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0853

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.0510

Gnomad NFE exome AF: 0.0637

Gnomad OTH exome AF: 0.0778

GnomAD4 exome AF: 0.0623 AC: 90796 AN: 1457788 Hom.: 3249 Cov.: 28 AF XY: 0.0638 AC XY: 46294 AN XY: 725526

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.0980

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0671

GnomAD4 genome AF: 0.0553 AC: 8414 AN: 152212 Hom.: 302 Cov.: 32 AF XY: 0.0567 AC XY: 4220 AN XY: 74428

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0882

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0442

Gnomad4 NFE AF: 0.0590

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.0486 Hom.: 87

Bravo AF: 0.0589

Asia WGS AF: 0.139 AC: 483 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs41275339; hg19: chr5-161277899;