rs75423500

Variant names:

• chr5-161854158-C-A
• rs75423500
• NM_001127644.2:c.75C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-161854158-C-A
• chr5-161854158-C-T

Variant summary

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

The NM_001127644.2(GABRA1):​c.75C>A​(p.Ser25Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GABRA1 NM_001127644.2 missense, splice_region
• Scores: Splicing: ADA: 0.00003396
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

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 the GABRA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.1498 (above the threshold of 3.09). Trascript score misZ: 4.2662 (above the threshold of 3.09). GenCC associations: The gene is linked to juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22149721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.75C>A	p.Ser25Arg	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.75C>A	p.Ser25Arg	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386324 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 693968

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: 9.57e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;.;T;T;T;T;T;.;.;T;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	.;.;T;.;.;.;T;.;T;T;.;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;L;.;L;L;L;.;L;.;.;L;.;.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.64	.;N;.;N;N;N;N;.;N;.;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.20	.;T;.;T;T;T;D;.;T;.;.;.;.;.
Sift4G	Benign	0.28	.;T;D;T;T;T;T;.;.;.;.;T;T;.
Polyphen		0.44	B;B;.;B;B;B;.;B;.;.;B;.;.;B
Vest4		0.64, 0.90, 0.64, 0.64
MutPred		0.34		Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);.;Gain of solvent accessibility (P = 0.0471);.;Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);
MVP		0.99
MPC		1.5
ClinPred		0.21	T
GERP RS		2.7
Varity_R		0.056
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0020
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: rs75423500; hg19: chr5-161281164;