rs1555383878

Variant names:

• chr15-26772467-G-A
• rs1555383878
• NM_000814.6:c.175C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_000814.6(GABRB3):​c.175C>T​(p.Pro59Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P59A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.61
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000814.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.39559034).
• BS2: High AC in GnomAdExome4 at 10 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000814.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	NM_000814.6	MANE Select	c.175C>T	p.Pro59Ser	missense splice_region	Exon 3 of 9	NP_000805.1
	GABRB3	NM_021912.5		c.175C>T	p.Pro59Ser	missense splice_region	Exon 3 of 9	NP_068712.1
	GABRB3	NM_001278631.2		c.-177C>T		splice_region	Exon 3 of 10	NP_001265560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.175C>T	p.Pro59Ser	missense splice_region	Exon 3 of 9	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.343C>T	p.Pro115Ser	missense splice_region	Exon 4 of 10	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.175C>T	p.Pro59Ser	missense splice_region	Exon 3 of 9	ENSP00000299267.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458070 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725330

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52568

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

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110334

Other (OTH) AF: 0.0000333 AC: 2 AN: 60150

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.26
Sift	Benign	0.074	T
Sift4G	Benign	0.26	T
Polyphen		0.0060	B
Vest4		0.090
MutPred		0.40		Loss of catalytic residue at P115 (P = 0.1268)
MVP		0.44
MPC		1.2
ClinPred		0.31	T
GERP RS		4.6
PromoterAI		-0.033	Neutral
Varity_R		0.27
gMVP		0.80
Mutation Taster		=53/47	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: rs1555383878; hg19: chr15-27017614;