Variant rs2229940 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000809.4(GABRA4):c.76C>A(p.Leu26Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,400 control chromosomes in the GnomAD database, including 99,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.31 ( 7884 hom., cov: 32)

Exomes 𝑓: 0.35 ( 91708 hom. )

Consequence

GABRA4
NM_000809.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

GABRA4 (HGNC:4078): (gamma-aminobutyric acid type A receptor subunit alpha4) Gamma-aminobutyric acid (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. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]

GABRA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041318536).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GABRA4	NM_000809.4 linkuse as main transcript	c.76C>A	p.Leu26Met	missense_variant	1/9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2 linkuse as main transcript	c.29+58C>A		intron_variant			NP_001191195.1
GABRA4	NM_001204267.2 linkuse as main transcript	c.29+58C>A		intron_variant			NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4 linkuse as main transcript	c.76C>A	p.Leu26Met	missense_variant	1/9	1	NM_000809.4	ENSP00000264318	P1

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47767

AN:

152016

Hom.:

7882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.334

GnomAD3 exomes

AF:

0.315

AC:

79059

AN:

250652

Hom.:

13194

AF XY:

0.315

AC XY:

42745

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.253

Gnomad AMR exome

AF:

0.280

Gnomad ASJ exome

AF:

0.396

Gnomad EAS exome

AF:

0.384

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.361

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.350

AC:

511581

AN:

1461266

Hom.:

91708

Cov.:

AF XY:

0.346

AC XY:

251529

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.254

Gnomad4 AMR exome

AF:

0.282

Gnomad4 ASJ exome

AF:

0.392

Gnomad4 EAS exome

AF:

0.358

Gnomad4 SAS exome

AF:

0.222

Gnomad4 FIN exome

AF:

0.230

Gnomad4 NFE exome

AF:

0.370

Gnomad4 OTH exome

AF:

0.346

GnomAD4 genome

AF:

0.314

AC:

47794

AN:

152134

Hom.:

7884

Cov.:

AF XY:

0.304

AC XY:

22595

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.251

Gnomad4 AMR

AF:

0.329

Gnomad4 ASJ

AF:

0.392

Gnomad4 EAS

AF:

0.362

Gnomad4 SAS

AF:

0.214

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.365

Gnomad4 OTH

AF:

0.336

Alfa

AF:

0.357

Hom.:

15292

Bravo

AF:

0.323

TwinsUK

AF:

0.381

AC:

1413

ALSPAC

AF:

0.382

AC:

1472

ESP6500AA

AF:

0.257

AC:

1132

ESP6500EA

AF:

0.367

AC:

3154

ExAC

AF:

0.314

AC:

38135

Asia WGS

AF:

0.268

AC:

933

AN:

3478

EpiCase

AF:

0.368

EpiControl

AF:

0.380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.81

PROVEAN

Benign

-0.40

REVEL

Benign

0.12

Sift

Uncertain

0.023

Sift4G

Uncertain

0.040

Polyphen

0.091

Vest4

0.28

MPC

1.6

ClinPred

0.021

GERP RS

3.0

Varity_R

0.16

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over