dbSNP rs7660336: GABRA4:c.*574C>G (chr4-46927651-G-C) – 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.*574C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 152,320 control chromosomes in the GnomAD database, including 20,804 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 0.52 ( 20751 hom., cov: 32)

Exomes 𝑓: 0.51 ( 53 hom. )

Consequence

GABRA4
NM_000809.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

Publications

10 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:58780):

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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000809.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GABRA4	NM_000809.4	MANE Select	c.*574C>G	3_prime_UTR	Exon 9 of 9	NP_000800.2
GABRA4	NM_001204266.2		c.*574C>G	3_prime_UTR	Exon 9 of 9	NP_001191195.1
GABRA4	NM_001204267.2		c.*574C>G	3_prime_UTR	Exon 8 of 8	NP_001191196.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.*574C>G	3_prime_UTR	Exon 9 of 9	ENSP00000264318.3
GABRA4	ENST00000900310.1		c.*574C>G	3_prime_UTR	Exon 8 of 8	ENSP00000570369.1
ENSG00000299086	ENST00000760386.1		n.173-793G>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

78970

AN:

151758

Hom.:

20717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.462

Gnomad AMR

AF:

0.565

Gnomad ASJ

AF:

0.464

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.550

Gnomad FIN

AF:

0.549

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.526

Gnomad OTH

AF:

0.503

GnomAD4 exome

AF:

0.514

AC:

228

AN:

444

Hom.:

Cov.:

AF XY:

0.507

AC XY:

139

AN XY:

274

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.750

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

0.535

AC:

199

AN:

372

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.355

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.521

AC:

79061

AN:

151876

Hom.:

20751

Cov.:

AF XY:

0.521

AC XY:

38668

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.474

AC:

19631

AN:

41438

American (AMR)

AF:

0.566

AC:

8614

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

1608

AN:

3468

East Asian (EAS)

AF:

0.662

AC:

3417

AN:

5162

South Asian (SAS)

AF:

0.548

AC:

2640

AN:

4814

European-Finnish (FIN)

AF:

0.549

AC:

5790

AN:

10540

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.526

AC:

35735

AN:

67912

Other (OTH)

AF:

0.505

AC:

1065

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1956

3912

5867

7823

9779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.402

Hom.:

1087

Bravo

AF:

0.519

Asia WGS

AF:

0.591

AC:

2051

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.51

(source)

DANN

Benign

0.62

PhyloP100

-0.031

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over