rs140683

Variant names:

• chr15-26943188-T-A
• rs140683
• NM_000810.4:c.878-27T>A

Your query was ambiguous. Multiple possible variants found:

• chr15-26943188-T-A
• chr15-26943188-T-C
• chr15-26943188-T-G

Variant summary

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

The NM_000810.4(GABRA5):​c.878-27T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,533,578 control chromosomes in the GnomAD database, including 144,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.37 (10921 hom., cov: 34)
  • Exomes 𝑓: 0.43 (133787 hom.)
• Consequence: GABRA5 NM_000810.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.129
• Publications: 6 publications found

Genes affected

GABRA5 (HGNC:4079): (gamma-aminobutyric acid type A receptor subunit alpha5) 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. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

GABRA5 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 79

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-26943188-T-A is Benign according to our data. Variant chr15-26943188-T-A is described in ClinVar as Benign. ClinVar VariationId is 1285289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.878-27T>A		intron_variant	Intron 9 of 10	ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.878-27T>A		intron_variant	Intron 9 of 10	1	NM_000810.4	ENSP00000335592.5
GABRA5	ENST00000355395.9	c.878-27T>A		intron_variant	Intron 8 of 9	5		ENSP00000347557.5
GABRA5	ENST00000400081.7	c.878-27T>A		intron_variant	Intron 9 of 10	5		ENSP00000382953.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55925 AN: 152032 Hom.: 10927 Cov.: 34

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.355

GnomAD2 exomes AF: 0.369 AC: 53836 AN: 145890 AF XY: 0.373

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.435 AC: 600267 AN: 1381430 Hom.: 133787 Cov.: 27 AF XY: 0.433 AC XY: 295013 AN XY: 680658

African (AFR) AF: 0.251 AC: 7830 AN: 31242

American (AMR) AF: 0.293 AC: 10349 AN: 35290

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 8902 AN: 24786

East Asian (EAS) AF: 0.201 AC: 7142 AN: 35508

South Asian (SAS) AF: 0.361 AC: 28411 AN: 78686

European-Finnish (FIN) AF: 0.426 AC: 18904 AN: 44418

Middle Eastern (MID) AF: 0.305 AC: 1560 AN: 5114

European-Non Finnish (NFE) AF: 0.462 AC: 494125 AN: 1069100

Other (OTH) AF: 0.402 AC: 23044 AN: 57286

GnomAD4 genome AF: 0.368 AC: 55936 AN: 152148 Hom.: 10921 Cov.: 34 AF XY: 0.364 AC XY: 27093 AN XY: 74402

African (AFR) AF: 0.253 AC: 10514 AN: 41526

American (AMR) AF: 0.350 AC: 5347 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1248 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1031 AN: 5164

South Asian (SAS) AF: 0.355 AC: 1710 AN: 4820

European-Finnish (FIN) AF: 0.429 AC: 4539 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30224 AN: 67972

Other (OTH) AF: 0.353 AC: 746 AN: 2112

Alfa AF: 0.397 Hom.: 2281

Bravo AF: 0.357

Asia WGS AF: 0.281 AC: 980 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 79 Benign:1

Aug 10, 2021

Genome-Nilou Lab

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	-0.81
CADD	Benign	6.6
DANN	Benign	0.53
PhyloP100		-0.13
BranchPoint Hunter		1.0
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: rs140683; hg19: chr15-27188335; COSMIC: COSV59487341; COSMIC: COSV59487341;