NM_000809.4:c.1087C>T

Variant names:

• chr4-46965017-G-A
• rs1722702199
• NM_000809.4:c.1087C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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

ACMG classification

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=0.12105882).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	NM_000809.4	MANE Select	c.1087C>T	p.Pro363Ser	missense	Exon 8 of 9	NP_000800.2
	GABRA4	NM_001204266.2		c.1030C>T	p.Pro344Ser	missense	Exon 8 of 9	NP_001191195.1
	GABRA4	NM_001204267.2		c.877C>T	p.Pro293Ser	missense	Exon 7 of 8	NP_001191196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA4	ENST00000264318.4	TSL:1 MANE Select	c.1087C>T	p.Pro363Ser	missense	Exon 8 of 9	ENSP00000264318.3	P48169
	GABRA4	ENST00000900310.1		c.934C>T	p.Pro312Ser	missense	Exon 7 of 8	ENSP00000570369.1
	GABRA4	ENST00000508560.5	TSL:3	n.*908C>T		non_coding_transcript_exon	Exon 8 of 9	ENSP00000425445.1	D6R924

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GABRA4-related Epileptic and Neurodevelopmental Disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.7
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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

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