rs1057519550

Variant names:

• chr15-26621403-T-G
• rs1057519550
• NM_000814.6:c.372A>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000814.6(GABRB3):​c.372A>C​(p.Leu124Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.03
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000814.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-26621403-T-G is Pathogenic according to our data. Variant chr15-26621403-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	NM_000814.6	MANE Select	c.372A>C	p.Leu124Phe	missense	Exon 4 of 9	NP_000805.1	P28472-1
	GABRB3	NM_021912.5		c.372A>C	p.Leu124Phe	missense	Exon 4 of 9	NP_068712.1	X5DQY4
	GABRB3	NM_001191321.3		c.159A>C	p.Leu53Phe	missense	Exon 2 of 7	NP_001178250.1	P28472-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.372A>C	p.Leu124Phe	missense	Exon 4 of 9	ENSP00000308725.5	P28472-1
	GABRB3	ENST00000541819.6	TSL:1	c.540A>C	p.Leu180Phe	missense	Exon 5 of 10	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000299267.9	TSL:1	c.372A>C	p.Leu124Phe	missense	Exon 4 of 9	ENSP00000299267.4	P28472-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

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	-	-	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.012
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.013	D
Polyphen		0.96	D
Vest4		0.80
MutPred		0.51		Gain of catalytic residue at L180 (P = 0.0058)
MVP		0.95
MPC		2.5
ClinPred		0.89	D
GERP RS		0.95
Varity_R		0.67
gMVP		0.90
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1057519550; hg19: chr15-26866550;