chr5-161854158-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000806.5(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. Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GABRA1 NM_000806.5 missense, splice_region
• Scores: Splicing: ADA: 0.00003396
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 2 publications found

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]

GABRA1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22149721).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000806.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	NM_001127644.2	MANE Select	c.75C>A	p.Ser25Arg	missense splice_region	Exon 3 of 10	NP_001121116.1
	GABRA1	NM_000806.5		c.75C>A	p.Ser25Arg	missense splice_region	Exon 4 of 11	NP_000797.2
	GABRA1	NM_001127643.2		c.75C>A	p.Ser25Arg	missense splice_region	Exon 4 of 11	NP_001121115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.75C>A	p.Ser25Arg	missense splice_region	Exon 3 of 10	ENSP00000377517.4
	GABRA1	ENST00000023897.10	TSL:1	c.75C>A	p.Ser25Arg	missense splice_region	Exon 4 of 11	ENSP00000023897.6
	GABRA1	ENST00000428797.7	TSL:1	c.75C>A	p.Ser25Arg	missense splice_region	Exon 4 of 11	ENSP00000393097.2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31746

American (AMR) AF: 0.00 AC: 0 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 39230

South Asian (SAS) AF: 0.00 AC: 0 AN: 83710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 9.57e-7 AC: 1 AN: 1045128

Other (OTH) AF: 0.00 AC: 0 AN: 57868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.41
Sift	Benign	0.20	T
Sift4G	Benign	0.28	T
Polyphen		0.44	B
Vest4		0.64
MutPred		0.34		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
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs75423500; hg19: chr5-161281164;