rs886037939

Variant names:

• chr15-26580456-T-A
• rs886037939
• NM_000814.6:c.545A>T

Your query was ambiguous. Multiple possible variants found:

• chr15-26580456-T-A
• chr15-26580456-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000814.6(GABRB3):​c.545A>T​(p.Tyr182Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABRB3 NM_000814.6 missense, splice_region
• Scores: Splicing: ADA: 0.3467
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GABRB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.3856 (above the threshold of 3.09). Trascript score misZ: 4.4544 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 15-26580456-T-A is Pathogenic according to our data. Variant chr15-26580456-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 254262.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-26580456-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.545A>T	p.Tyr182Phe	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.545A>T	p.Tyr182Phe	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 43 Pathogenic:1

Sep 12, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;.;D;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.7	.;L;.;.;L;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	.;D;.;D;D;.;.;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	.;D;.;D;D;.;.;D;D
Sift4G	Uncertain	0.027	D;D;D;T;D;.;.;D;D
Polyphen		0.92, 0.96, 0.96	.;P;.;D;D;.;.;.;.
Vest4		0.66
MutPred		0.81		.;.;.;Loss of phosphorylation at Y238 (P = 0.0577);.;.;.;.;.;
MVP		0.78
MPC		2.2
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.35
dbscSNV1_RF	Benign	0.54
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: rs886037939; hg19: chr15-26825603;