4-46928732-C-T

Variant names:

• chr4-46928732-C-T
• NM_000809.4:c.1158G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 16/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1792284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA4	NM_000809.4	c.1158G>A	p.Met386Ile	missense_variant	Exon 9 of 9	ENST00000264318.4	NP_000800.2
GABRA4	NM_001204266.2	c.1101G>A	p.Met367Ile	missense_variant	Exon 9 of 9		NP_001191195.1
GABRA4	NM_001204267.2	c.948G>A	p.Met316Ile	missense_variant	Exon 8 of 8		NP_001191196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA4	ENST00000264318.4	c.1158G>A	p.Met386Ile	missense_variant	Exon 9 of 9	1	NM_000809.4	ENSP00000264318.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.27
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.48		Loss of MoRF binding (P = 0.1063);
MVP		0.49
MPC		0.069
ClinPred		0.29	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-46930749;