4-46926817-C-T

Variant names:

• chr4-46926817-C-T
• rs17599102
• NM_000809.4:c.*1408G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.*1408G>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 0.254 in 151,672 control chromosomes in the GnomAD database, including 5,039 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 0.25 (5039 hom., cov: 31)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: GABRA4 NM_000809.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• Publications: 8 publications found

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

ENSG00000299086 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.*1408G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.*1408G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001191195.1
GABRA4	NM_001204267.2	c.*1408G>A		3_prime_UTR_variant	Exon 8 of 8		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.*1408G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000809.4	ENSP00000264318.3
ENSG00000299086	ENST00000760386.1	n.173-1627C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38551 AN: 151548 Hom.: 5034 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ 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.

GnomAD4 genome AF: 0.254 AC: 38580 AN: 151668 Hom.: 5039 Cov.: 31 AF XY: 0.246 AC XY: 18257 AN XY: 74136

African (AFR) AF: 0.246 AC: 10206 AN: 41406

American (AMR) AF: 0.200 AC: 3042 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3468

East Asian (EAS) AF: 0.288 AC: 1486 AN: 5158

South Asian (SAS) AF: 0.186 AC: 893 AN: 4814

European-Finnish (FIN) AF: 0.170 AC: 1799 AN: 10570

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.284 AC: 19274 AN: 67748

Other (OTH) AF: 0.256 AC: 539 AN: 2106

Alfa AF: 0.214 Hom.: 836

Bravo AF: 0.256

Asia WGS AF: 0.212 AC: 736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.32
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17599102; hg19: chr4-46928834;