15-26869291-C-T

Position:

• chr15-26869291-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000810.4(GABRA5):​c.43C>T​(p.Leu15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GABRA5 NM_000810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

GABRA5 (HGNC:4079): (gamma-aminobutyric acid type A receptor subunit alpha5) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. Transcript variants utilizing three different alternative non-coding first exons have been described. [provided by RefSeq, Jul 2008]

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]

GABRA5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRA5. . Gene score misZ 3.2308 (greater than the threshold 3.09). Trascript score misZ 3.2557 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 79.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16923165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA5	NM_000810.4	c.43C>T	p.Leu15Phe	missense_variant	3/11	ENST00000335625.10	NP_000801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA5	ENST00000335625.10	c.43C>T	p.Leu15Phe	missense_variant	3/11	1	NM_000810.4	ENSP00000335592.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457582 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 725516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2024

The c.43C>T (p.L15F) alteration is located in exon 3 (coding exon 1) of the GABRA5 gene. This alteration results from a C to T substitution at nucleotide position 43, causing the leucine (L) at amino acid position 15 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.0038	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T;.;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.67	.;.;T;T;T;.;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N;N;N;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.86	N;N;N;N;N;D;N
REVEL	Benign	0.20
Sift	Benign	0.14	T;T;T;T;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T;.;T
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.16
MutPred		0.50		Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);
MVP		0.71
MPC		0.94
ClinPred		0.28	T
GERP RS		3.8
Varity_R		0.092
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1892404389; hg19: chr15-27114438;