ENST00000299267.9:c.44C>T

Variant names:

• chr15-26773681-G-A
• rs121913126
• ENST00000299267.9:c.44C>T
• GABRB3 p.Ser15Phe

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000299267.9(GABRB3):​c.44C>T​(p.Ser15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,575,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S15C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: GABRB3 ENST00000299267.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: -0.573
• Publications: 17 publications found

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07929245).
• BP6: Variant 15-26773681-G-A is Benign according to our data. Variant chr15-26773681-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16192.
• BS2: High AC in GnomAd4 at 23 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000299267.9. 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
	GABRB3	NM_021912.5		c.44C>T	p.Ser15Phe	missense	Exon 1 of 9	NP_068712.1	X5DQY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000299267.9	TSL:1	c.44C>T	p.Ser15Phe	missense	Exon 1 of 9	ENSP00000299267.4	P28472-2
	GABRB3	ENST00000541819.6	TSL:1	c.249-909C>T		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000638099.1	TSL:5	c.-20+262C>T		intron	N/A	ENSP00000490678.1	A0A1B0GVW3

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000985 AC: 18 AN: 182676 AF XY: 0.0000910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000670

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000492 AC: 70 AN: 1423486 Hom.: 0 Cov.: 32 AF XY: 0.0000525 AC XY: 37 AN XY: 704324

African (AFR) AF: 0.00 AC: 0 AN: 32802

American (AMR) AF: 0.000510 AC: 20 AN: 39198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 37842

South Asian (SAS) AF: 0.00 AC: 0 AN: 81022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.0000430 AC: 47 AN: 1093600

Other (OTH) AF: 0.0000509 AC: 3 AN: 58952

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000544 Hom.: 0

Bravo AF: 0.000147

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	-	Epilepsy, childhood absence, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.57
PROVEAN	Benign	0.18	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.23	T
PromoterAI		0.00060	Neutral
Mutation Taster		=82/18	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121913126;

hg19: chr15-27018828;