4-46992955-GAAAA-GAAAAA

Variant names:

• chr4-46992955-G-GA
• rs3215202
• NM_000809.4:c.87-10dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000809.4(GABRA4):​c.87-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (7443 hom., cov: 0)
  • Exomes 𝑓: 0.34 (10842 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABRA4 NM_000809.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 4-46992955-G-GA is Benign according to our data. Variant chr4-46992955-G-GA is described in ClinVar as [Benign]. Clinvar id is 402889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.87-10dupT		intron_variant	Intron 1 of 8	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.30-10dupT		intron_variant	Intron 1 of 8		NP_001191195.1
GABRA4	NM_001204267.2	c.30-10dupT		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.87-10dupT		intron_variant	Intron 1 of 8	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes AF: 0.322 AC: 46381 AN: 143904 Hom.: 7447 Cov.: 0

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.360 AC: 62122 AN: 172330 AF XY: 0.359

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.376

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.375

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.344 AC: 371495 AN: 1079110 Hom.: 10842 Cov.: 19 AF XY: 0.344 AC XY: 186642 AN XY: 543316

African (AFR) AF: 0.306 AC: 7513 AN: 24544

American (AMR) AF: 0.350 AC: 11165 AN: 31912

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 7869 AN: 20960

East Asian (EAS) AF: 0.336 AC: 11006 AN: 32746

South Asian (SAS) AF: 0.283 AC: 18640 AN: 65946

European-Finnish (FIN) AF: 0.291 AC: 11827 AN: 40682

Middle Eastern (MID) AF: 0.363 AC: 1657 AN: 4568

European-Non Finnish (NFE) AF: 0.352 AC: 285816 AN: 812254

Other (OTH) AF: 0.352 AC: 16002 AN: 45498

GnomAD4 genome AF: 0.322 AC: 46393 AN: 143958 Hom.: 7443 Cov.: 0 AF XY: 0.312 AC XY: 21751 AN XY: 69624

African (AFR) AF: 0.280 AC: 10943 AN: 39150

American (AMR) AF: 0.333 AC: 4838 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1342 AN: 3410

East Asian (EAS) AF: 0.336 AC: 1642 AN: 4884

South Asian (SAS) AF: 0.225 AC: 1003 AN: 4460

European-Finnish (FIN) AF: 0.201 AC: 1707 AN: 8504

Middle Eastern (MID) AF: 0.408 AC: 115 AN: 282

European-Non Finnish (NFE) AF: 0.362 AC: 23859 AN: 65858

Other (OTH) AF: 0.338 AC: 675 AN: 1996

Alfa AF: 0.234 Hom.: 91

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.026
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: rs3215202; hg19: chr4-46994972;