rs1064794797

Variant names:

• chr15-26772403-A-C
• rs1064794797
• NM_000814.6:c.239T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-26772403-A-C
• chr15-26772403-A-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.09
• 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 11 ACMG points.

• PM1: In a hotspot region, there are 2 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-26772403-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420927.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 15-26772403-A-C is Pathogenic according to our data. Variant chr15-26772403-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559623.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	Exon 3 of 9		NP_068712.1
GABRB3	NM_001278631.2	c.-113T>G		splice_region_variant	Exon 3 of 10		NP_001265560.1
GABRB3	NM_001278631.2	c.-113T>G		5_prime_UTR_variant	Exon 3 of 10		NP_001265560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.239T>G	p.Met80Arg	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 43 Pathogenic:1

Aug 31, 2017

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35599849) -

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

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		5.1
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
PromoterAI		-0.089	Neutral
Varity_R		0.97
gMVP		0.99
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs1064794797; hg19: chr15-27017550;