rs10517173

Variant names:

• chr4-46980479-A-C
• rs10517173
• NM_000809.4:c.206-1381T>G

Variant summary

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

The NM_000809.4(GABRA4):​c.206-1381T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,048 control chromosomes in the GnomAD database, including 915 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 0.11 (915 hom., cov: 32)
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.206-1381T>G		intron_variant	Intron 2 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.149-1381T>G		intron_variant	Intron 2 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.149-1381T>G		intron_variant	Intron 2 of 7		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.206-1381T>G		intron_variant	Intron 2 of 8	1	NM_000809.4	ENSP00000264318.3
GABRA4	ENST00000502874.1	n.87-1381T>G		intron_variant	Intron 1 of 5	5		ENSP00000424386.1
GABRA4	ENST00000508560.5	n.*27-1381T>G		intron_variant	Intron 2 of 8	3		ENSP00000425445.1
GABRA4	ENST00000511523.5	n.*27-1381T>G		intron_variant	Intron 2 of 7	3		ENSP00000422152.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15983 AN: 151934 Hom.: 912 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0962

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.0970

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0957

Gnomad OTH AF: 0.0999

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

GnomAD4 genome AF: 0.105 AC: 15995 AN: 152048 Hom.: 915 Cov.: 32 AF XY: 0.106 AC XY: 7888 AN XY: 74304

African (AFR) AF: 0.122 AC: 5080 AN: 41498

American (AMR) AF: 0.0842 AC: 1284 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3466

East Asian (EAS) AF: 0.0964 AC: 495 AN: 5136

South Asian (SAS) AF: 0.187 AC: 903 AN: 4834

European-Finnish (FIN) AF: 0.0970 AC: 1026 AN: 10582

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0957 AC: 6501 AN: 67956

Other (OTH) AF: 0.101 AC: 213 AN: 2114

Alfa AF: 0.105 Hom.: 176

Bravo AF: 0.101

Asia WGS AF: 0.142 AC: 493 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		0.18
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: rs10517173; hg19: chr4-46982496;