rs759523853

Variant names:

• chr1-2019430-G-A
• rs759523853
• NM_000815.5:c.7G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2019430-G-A
• chr1-2019430-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 15/22 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.361
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 10

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000233542 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062045723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000815.5. 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
	GABRD	NM_000815.5	MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 9	NP_000806.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	ENST00000378585.7	TSL:1 MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 9	ENSP00000367848.4	O14764
	GABRD	ENST00000638771.1	TSL:3	c.7G>A	p.Ala3Thr	missense	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
	GABRD	ENST00000640067.1	TSL:5	c.7G>A	p.Ala3Thr	missense	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.000319 AC: 1 AN: 3134 AF XY: 0.000505

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 943180 Hom.: 0 Cov.: 30 AF XY: 0.00000224 AC XY: 1 AN XY: 445868

African (AFR) AF: 0.00 AC: 0 AN: 18162

American (AMR) AF: 0.00 AC: 0 AN: 4452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8444

East Asian (EAS) AF: 0.00 AC: 0 AN: 10908

South Asian (SAS) AF: 0.00 AC: 0 AN: 21388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2158

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833390

Other (OTH) AF: 0.00 AC: 0 AN: 33760

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.36
PrimateAI	Pathogenic	0.83	D
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)
MVP		0.41
MPC		0.73
ClinPred		0.042	T
GERP RS		0.34
PromoterAI		-0.11	Neutral
Varity_R		0.079
gMVP		0.39
Mutation Taster		=92/8	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: rs759523853; hg19: chr1-1950869;