dbSNP rs759523853: GABRD:p.Ala3Thr (chr1-2019430-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000815.5(GABRD):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 943,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A3S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.361

Variant links:

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]

GABRD links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062045723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 9	ENST00000378585.7	NP_000806.2	O14764A8K496

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000319

AC:

AN:

3134

Hom.:

AF XY:

0.000505

AC XY:

AN XY:

1982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00244

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000106

AC:

AN:

943180

Hom.:

Cov.:

AF XY:

0.00000224

AC XY:

AN XY:

445868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.35

T;T;T;T;T

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.062

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.20

N;.;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.040

N;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.33

T;.;.;.;.

Sift4G

Benign

0.61

T;.;.;.;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.13

MutPred

0.23

Gain of phosphorylation at A3 (P = 0.018);Gain of phosphorylation at A3 (P = 0.018);Gain of phosphorylation at A3 (P = 0.018);Gain of phosphorylation at A3 (P = 0.018);Gain of phosphorylation at A3 (P = 0.018);

MVP

0.41

MPC

0.73

ClinPred

0.042

GERP RS

0.34

Varity_R

0.079

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over