rs749316684

Positions:

• chr1-2029730-G-A
• chr1-2029730-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000815.5(GABRD):​c.1027G>A​(p.Ala343Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. A343P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GABRD NM_000815.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62

Genes affected

GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) 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. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

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=0.24440938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRD	NM_000815.5	c.1027G>A	p.Ala343Thr	missense_variant	8/9	ENST00000378585.7
GABRD	XM_017000936.2	c.1732G>A	p.Ala578Thr	missense_variant	7/8
GABRD	XM_011541194.4	c.1066G>A	p.Ala356Thr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7	c.1027G>A	p.Ala343Thr	missense_variant	8/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.3	L;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.80	N;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.49	T;.;.;.;.
Sift4G	Benign	0.56	T;.;.;.;.
Polyphen		0.82	P;.;.;.;.
Vest4		0.17
MutPred		0.36		Gain of phosphorylation at A343 (P = 0.0461);.;Gain of phosphorylation at A343 (P = 0.0461);.;.;
MVP		0.80
MPC		1.0
ClinPred		0.75	D
GERP RS		4.0
Varity_R		0.065
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs749316684; hg19: chr1-1961169;