rs7685553

Positions:

• chr4-46951480-T-C
• chr4-46951480-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000809.4(GABRA4):​c.1134+13490A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 151,718 control chromosomes in the GnomAD database, including 1,745 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 0.15 (1745 hom., cov: 31)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.932

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.1134+13490A>G		intron_variant		ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.1077+13490A>G		intron_variant			NP_001191195.1
GABRA4	NM_001204267.2	c.924+13490A>G		intron_variant			NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.1134+13490A>G		intron_variant		1	NM_000809.4	ENSP00000264318	P1
GABRA4	ENST00000508560.5	c.*955+13490A>G		intron_variant, NMD_transcript_variant		3		ENSP00000425445
GABRA4	ENST00000511523.5	c.*802+13490A>G		intron_variant, NMD_transcript_variant		3		ENSP00000422152

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22034 AN: 151606 Hom.: 1738 Cov.: 31

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0686

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.126

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.145 AC: 22061 AN: 151718 Hom.: 1745 Cov.: 31 AF XY: 0.145 AC XY: 10757 AN XY: 74116

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0690

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.128

Alfa AF: 0.165 Hom.: 274

Bravo AF: 0.138

Asia WGS AF: 0.174 AC: 605 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs7685553; hg19: chr4-46953497;