4-46965041-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000809.4(GABRA4):c.1063A>G(p.Thr355Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,612,096 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: GABRA4 NM_000809.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0120

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0096030235).
• BP6: Variant 4-46965041-T-C is Benign according to our data. Variant chr4-46965041-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3041389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA4	NM_000809.4	c.1063A>G	p.Thr355Ala	missense_variant	8/9	ENST00000264318.4
GABRA4	NM_001204266.2	c.1006A>G	p.Thr336Ala	missense_variant	8/9
GABRA4	NM_001204267.2	c.853A>G	p.Thr285Ala	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.1063A>G	p.Thr355Ala	missense_variant	8/9	1	NM_000809.4	P1
GABRA4	ENST00000508560.5	c.*884A>G		3_prime_UTR_variant, NMD_transcript_variant	8/9	3
GABRA4	ENST00000511523.5	c.*731A>G		3_prime_UTR_variant, NMD_transcript_variant	7/8	3

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 151746 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00159 AC: 397 AN: 250466 Hom.: 0 AF XY: 0.00158 AC XY: 214 AN XY: 135376

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.000495

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00333 AC: 4868 AN: 1460232 Hom.: 10 Cov.: 31 AF XY: 0.00315 AC XY: 2289 AN XY: 726408

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.000516

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00423

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00190 AC: 289 AN: 151864 Hom.: 0 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74224

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00326 Hom.: 2

Bravo AF: 0.00181

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00328

EpiControl AF: 0.00226

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GABRA4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.1
Dann	Benign	0.16
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.050
MVP		0.41
MPC		0.054
ClinPred		0.0028	T
GERP RS		-3.7
Varity_R		0.025
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs45546331; hg19: chr4-46967058;