dbSNP rs2229940: GABRA4:p.Leu26Met (chr4-46993349-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Illumina

GABRA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GABRA4	NM_000809.4 link	c.76C>A	p.Leu26Met	missense_variant	Exon 1 of 9	ENST00000264318.4	NP_000800.2	P48169X5D7F5
GABRA4	NM_001204266.2 link	c.29+58C>A		intron_variant	Intron 1 of 8		NP_001191195.1	P48169
GABRA4	NM_001204267.2 link	c.29+58C>A		intron_variant	Intron 1 of 7		NP_001191196.1	P48169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4 link	c.76C>A	p.Leu26Met	missense_variant	Exon 1 of 9	1	NM_000809.4	ENSP00000264318.3		P48169

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

GnomAD2 exomes

AF:

0.315

AC:

79059

AN:

250652

AF XY:

0.315

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 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

African (AFR)

AF:

0.254

AC:

8508

AN:

33470

American (AMR)

AF:

0.282

AC:

12600

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

10233

AN:

26136

East Asian (EAS)

AF:

0.358

AC:

14206

AN:

39696

South Asian (SAS)

AF:

0.222

AC:

19104

AN:

86238

European-Finnish (FIN)

AF:

0.230

AC:

12294

AN:

53412

Middle Eastern (MID)

AF:

0.379

AC:

2186

AN:

5768

European-Non Finnish (NFE)

AF:

0.370

AC:

411543

AN:

1111444

Other (OTH)

AF:

0.346

AC:

20907

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

17291

34582

51873

69164

86455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13014

26028

39042

52056

65070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.314

AC:

47794

AN:

152134

Hom.:

7884

Cov.:

AF XY:

0.304

AC XY:

22595

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.251

AC:

10439

AN:

41528

American (AMR)

AF:

0.329

AC:

5027

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

1361

AN:

3472

East Asian (EAS)

AF:

0.362

AC:

1857

AN:

5134

South Asian (SAS)

AF:

0.214

AC:

1032

AN:

4824

European-Finnish (FIN)

AF:

0.205

AC:

2173

AN:

10598

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24800

AN:

67954

Other (OTH)

AF:

0.336

AC:

710

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1691

3382

5073

6764

8455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.351

Hom.:

29757

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

(source)

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

PhyloP100

2.9

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

PromoterAI

0.089

Neutral

(source)

Varity_R

0.16

gMVP

0.43

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over