Genetic Variant NM_000809.4:c.87-11_87-10delTT (chr4-46992955-GAA-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000809.4(GABRA4):c.87-11_87-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,299,454 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

GABRA4
NM_000809.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.167

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 21 AD gene.

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.87-11_87-10delTT	intron	N/A	NP_000800.2
GABRA4	NM_001204266.2		c.30-11_30-10delTT	intron	N/A	NP_001191195.1
GABRA4	NM_001204267.2		c.30-11_30-10delTT	intron	N/A	NP_001191196.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.87-11_87-10delTT	intron	N/A	ENSP00000264318.3
GABRA4	ENST00000502874.1	TSL:5	n.86+382_86+383delTT	intron	N/A	ENSP00000424386.1
GABRA4	ENST00000508560.5	TSL:3	n.19-11_19-10delTT	intron	N/A	ENSP00000425445.1

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

144084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000687

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000418

AC:

AN:

172330

AF XY:

0.000384

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000228

Gnomad FIN exome

AF:

0.0000702

Gnomad NFE exome

AF:

0.000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000228

AC:

263

AN:

1155314

Hom.:

AF XY:

0.000212

AC XY:

124

AN XY:

584308

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000716

AC:

AN:

26538

American (AMR)

AF:

0.000136

AC:

AN:

36780

Ashkenazi Jewish (ASJ)

AF:

0.0000443

AC:

AN:

22598

East Asian (EAS)

AF:

0.0000835

AC:

AN:

35944

South Asian (SAS)

AF:

0.000323

AC:

AN:

74382

European-Finnish (FIN)

AF:

0.0000850

AC:

AN:

47048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4806

European-Non Finnish (NFE)

AF:

0.000223

AC:

191

AN:

857952

Other (OTH)

AF:

0.000325

AC:

AN:

49266

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.267

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000146

AC:

AN:

144140

Hom.:

Cov.:

AF XY:

0.0000860

AC XY:

AN XY:

69730

show subpopulations

African (AFR)

AF:

0.000485

AC:

AN:

39190

American (AMR)

AF:

0.0000686

AC:

AN:

14574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

4894

South Asian (SAS)

AF:

0.000224

AC:

AN:

4464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65926

Other (OTH)

AF:

0.00

AC:

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00103

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism

(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