chr4-46992955-G-GAA

Variant names:

• chr4-46992955-G-GAA
• rs3215202
• NM_000809.4:c.87-11_87-10dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000809.4(GABRA4):​c.87-11_87-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 0)
  • Exomes 𝑓: 0.029 (26 hom.)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0142 (2053/144080) while in subpopulation EAS AF = 0.0405 (198/4890). AF 95% confidence interval is 0.0359. There are 25 homozygotes in GnomAd4. There are 978 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2053 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.87-11_87-10dupTT		intron_variant	Intron 1 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.30-11_30-10dupTT		intron_variant	Intron 1 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.30-11_30-10dupTT		intron_variant	Intron 1 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.87-11_87-10dupTT		intron_variant	Intron 1 of 8	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2043 AN: 144024 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00920

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00381

Gnomad EAS AF: 0.0406

Gnomad SAS AF: 0.00624

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0275 AC: 4743 AN: 172330 AF XY: 0.0269

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.0609

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0273

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0290 AC: 32859 AN: 1133516 Hom.: 26 Cov.: 19 AF XY: 0.0283 AC XY: 16241 AN XY: 573028

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

African (AFR) AF: 0.0281 AC: 735 AN: 26144

American (AMR) AF: 0.0195 AC: 703 AN: 36102

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 569 AN: 21864

East Asian (EAS) AF: 0.0519 AC: 1812 AN: 34902

South Asian (SAS) AF: 0.0143 AC: 1048 AN: 73362

European-Finnish (FIN) AF: 0.0168 AC: 779 AN: 46474

Middle Eastern (MID) AF: 0.0257 AC: 121 AN: 4716

European-Non Finnish (NFE) AF: 0.0305 AC: 25702 AN: 841752

Other (OTH) AF: 0.0288 AC: 1390 AN: 48200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0142 AC: 2053 AN: 144080 Hom.: 25 Cov.: 0 AF XY: 0.0140 AC XY: 978 AN XY: 69690

African (AFR) AF: 0.0171 AC: 669 AN: 39180

American (AMR) AF: 0.0139 AC: 202 AN: 14570

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 13 AN: 3410

East Asian (EAS) AF: 0.0405 AC: 198 AN: 4890

South Asian (SAS) AF: 0.00627 AC: 28 AN: 4464

European-Finnish (FIN) AF: 0.0106 AC: 90 AN: 8524

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.0123 AC: 813 AN: 65894

Other (OTH) AF: 0.0155 AC: 31 AN: 1996

Alfa AF: 0.0278 Hom.: 91

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.026
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3215202; hg19: chr4-46994972;