Genetic Variant GABRA4:p.Met386Ile (chr4-46928732-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000809.4(GABRA4):c.1158G>A(p.Met386Ile) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA4
NM_000809.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1792284).

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.1158G>A	p.Met386Ile	missense	Exon 9 of 9	NP_000800.2
GABRA4	NM_001204266.2		c.1101G>A	p.Met367Ile	missense	Exon 9 of 9	NP_001191195.1
GABRA4	NM_001204267.2		c.948G>A	p.Met316Ile	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.1158G>A	p.Met386Ile	missense	Exon 9 of 9	ENSP00000264318.3	P48169
GABRA4	ENST00000900310.1		c.1005G>A	p.Met335Ile	missense	Exon 8 of 8	ENSP00000570369.1
GABRA4	ENST00000508560.5	TSL:3	n.*979G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000425445.1	D6R924

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

0.0016

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.15

Eigen

Benign

-0.20

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.026

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.34

PhyloP100

2.3

PrimateAI

Benign

0.40

PROVEAN

Benign

0.040

REVEL

Benign

0.27

Sift

Benign

0.31

Sift4G

Benign

0.56

Polyphen

0.0020

Vest4

0.20

MutPred

0.48

Loss of MoRF binding (P = 0.1063)

MVP

0.49

MPC

0.069

ClinPred

0.29

GERP RS

5.6

Varity_R

0.22

gMVP

0.23

Mutation Taster

=85/15

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