Genetic Variant GABRA4:p.Val478Leu (chr4-46928458-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000809.4(GABRA4):c.1432G>C(p.Val478Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V478M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA4
NM_000809.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

Publications

3 publications found

Variant links:

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

GABRA4 links:

ENSG00000299086 (HGNC:58780):

ENSG00000299086 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023606002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000809.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRA4	NM_000809.4	MANE Select	c.1432G>C	p.Val478Leu	missense	Exon 9 of 9	NP_000800.2
GABRA4	NM_001204266.2		c.1375G>C	p.Val459Leu	missense	Exon 9 of 9	NP_001191195.1
GABRA4	NM_001204267.2		c.1222G>C	p.Val408Leu	missense	Exon 8 of 8	NP_001191196.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.1432G>C	p.Val478Leu	missense	Exon 9 of 9	ENSP00000264318.3	P48169
GABRA4	ENST00000900310.1		c.1279G>C	p.Val427Leu	missense	Exon 8 of 8	ENSP00000570369.1
GABRA4	ENST00000508560.5	TSL:3	n.*1253G>C		non_coding_transcript_exon	Exon 9 of 9	ENSP00000425445.1	D6R924

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.020

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.087

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.52

M_CAP

Benign

0.026

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.83

PhyloP100

0.69

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.020

REVEL

Benign

0.16

Sift

Benign

0.48

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.022

MutPred

0.40

Loss of loop (P = 0.0374)

MVP

0.21

MPC

0.055

ClinPred

0.62

GERP RS

2.2

Varity_R

0.055

gMVP

0.23

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over