Genetic Variant GABRA1:p.Ile72Met (chr5-161865749-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001127644.2(GABRA1):c.216C>G(p.Ile72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I72L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GABRA1
NM_001127644.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.39

Publications

0 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
epilepsy
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

GABRA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a topological_domain Extracellular (size 225) in uniprot entity GBRA1_HUMAN there are 33 pathogenic changes around while only 10 benign (77%) in NM_001127644.2

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127644.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRA1	NM_001127644.2	MANE Select	c.216C>G	p.Ile72Met	missense	Exon 4 of 10	NP_001121116.1	P14867
GABRA1	NM_000806.5		c.216C>G	p.Ile72Met	missense	Exon 5 of 11	NP_000797.2	A8K177
GABRA1	NM_001127643.2		c.216C>G	p.Ile72Met	missense	Exon 5 of 11	NP_001121115.1	P14867

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.216C>G	p.Ile72Met	missense	Exon 4 of 10	ENSP00000377517.4	P14867
GABRA1	ENST00000023897.10	TSL:1	c.216C>G	p.Ile72Met	missense	Exon 5 of 11	ENSP00000023897.6	P14867
GABRA1	ENST00000428797.7	TSL:1	c.216C>G	p.Ile72Met	missense	Exon 5 of 11	ENSP00000393097.2	P14867

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

-0.029

MutationAssessor

Uncertain

2.1

PhyloP100

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.70

Sift

Benign

0.13

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.88

MutPred

0.58

Gain of catalytic residue at V68 (P = 0.0235)

MVP

0.95

MPC

1.4

ClinPred

0.73

GERP RS

3.5

Varity_R

0.34

gMVP

0.91

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over