4-46965017-G-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.1087C>T(p.Pro363Ser) 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: 1.74

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=0.12105882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA4	NM_000809.4	c.1087C>T	p.Pro363Ser	missense_variant	8/9	ENST00000264318.4
GABRA4	NM_001204266.2	c.1030C>T	p.Pro344Ser	missense_variant	8/9
GABRA4	NM_001204267.2	c.877C>T	p.Pro293Ser	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.1087C>T	p.Pro363Ser	missense_variant	8/9	1	NM_000809.4	P1
GABRA4	ENST00000508560.5	c.*908C>T		3_prime_UTR_variant, NMD_transcript_variant	8/9	3
GABRA4	ENST00000511523.5	c.*755C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

GABRA4-related Epileptic and Neurodevelopmental Disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Aug 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.38
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.096
Sift	Benign	0.24	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.074
MutPred		0.34		Gain of helix (P = 0.0225);
MVP		0.37
MPC		0.056
ClinPred		0.10	T
GERP RS		0.92
Varity_R		0.025
gMVP		0.27

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: rs1722702199; hg19: chr4-46967034; COSMIC: COSV51924220;