dbSNP rs6447517: GABRA4:c.*1496T>A (chr4-46926729-A-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.*1496T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 151,622 control chromosomes in the GnomAD database, including 11,082 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11082 hom., cov: 31)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

GABRA4
NM_000809.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0150

Publications

8 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:

ENSG00000299086 (HGNC:):

ENSG00000299086 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 (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4 link	c.*1496T>A	3_prime_UTR_variant	Exon 9 of 9	ENST00000264318.4	NP_000800.2	P48169X5D7F5
GABRA4	NM_001204266.2 link	c.*1496T>A	3_prime_UTR_variant	Exon 9 of 9		NP_001191195.1	P48169
GABRA4	NM_001204267.2 link	c.*1496T>A	3_prime_UTR_variant	Exon 8 of 8		NP_001191196.1	P48169

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4 link	c.*1496T>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000809.4	ENSP00000264318.3		P48169
ENSG00000299086	ENST00000760386.1 link	n.173-1715A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

57102

AN:

151496

Hom.:

11077

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.359

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.368

GnomAD4 exome

AF:

0.125

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.377

AC:

57134

AN:

151614

Hom.:

11082

Cov.:

AF XY:

0.369

AC XY:

27344

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.338

AC:

13999

AN:

41408

American (AMR)

AF:

0.280

AC:

4250

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1433

AN:

3458

East Asian (EAS)

AF:

0.357

AC:

1835

AN:

5136

South Asian (SAS)

AF:

0.437

AC:

2103

AN:

4810

European-Finnish (FIN)

AF:

0.328

AC:

3463

AN:

10550

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.425

AC:

28780

AN:

67740

Other (OTH)

AF:

0.371

AC:

782

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1766

3532

5297

7063

8829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.407

Hom.:

1632

Bravo

AF:

0.367

Asia WGS

AF:

0.378

AC:

1315

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.0

(source)

DANN

Benign

0.42

PhyloP100

-0.015

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over