rs1064794797

chr15-26772403-A-Cchr15-26772403-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000814.6(GABRB3):c.239T>G(p.Met80Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 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. M80T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GABRB3 NM_000814.6 missense, splice_region
• Scores: Splicing: ADA: 0.8741
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Extracellular (size 219) in uniprot entity GBRB3_HUMAN there are 39 pathogenic changes around while only 7 benign (85%) in NM_000814.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-26772404-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2949842.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GABRB3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB3	NM_000814.6	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	3/9	ENST00000311550.10
GABRB3	NM_021912.5	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	3/9
GABRB3	NM_001278631.2	c.-113T>G		splice_region_variant, 5_prime_UTR_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB3	ENST00000311550.10	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	3/9	1	NM_000814.6	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 43 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Aug 31, 2017

- -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.4	M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		0.98	D;D;P;.
Vest4		0.70
MutPred		0.81		.;Loss of stability (P = 0.0348);.;.;
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.73
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

Other links and lift over

dbSNP: rs1064794797; hg19: chr15-27017550;