4-46928595-C-T

Variant names:

• chr4-46928595-C-T
• rs755684993
• NM_000809.4:c.1295G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000809.4(GABRA4):​c.1295G>A​(p.Ser432Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S432T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABRA4 NM_000809.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77
• Publications: 3 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

ENSG00000299086 (HGNC:58780):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31754956).

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.1295G>A	p.Ser432Asn	missense	Exon 9 of 9	NP_000800.2
	GABRA4	NM_001204266.2		c.1238G>A	p.Ser413Asn	missense	Exon 9 of 9	NP_001191195.1
	GABRA4	NM_001204267.2		c.1085G>A	p.Ser362Asn	missense	Exon 8 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.1295G>A	p.Ser432Asn	missense	Exon 9 of 9	ENSP00000264318.3	P48169
	GABRA4	ENST00000900310.1		c.1142G>A	p.Ser381Asn	missense	Exon 8 of 8	ENSP00000570369.1
	GABRA4	ENST00000508560.5	TSL:3	n.*1116G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000425445.1	D6R924

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251074 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461530 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727070

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.023	D
Sift4G	Benign	0.24	T
Polyphen		0.92	P
Vest4		0.37
MutPred		0.29		Loss of phosphorylation at S432 (P = 0.0147)
MVP		0.51
MPC		0.35
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.51
Mutation Taster		=70/30	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: rs755684993; hg19: chr4-46930612;