rs1060499553

Variant names:

• chr5-161890983-G-A
• rs1060499553
• NM_001127644.2:c.789G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001127644.2(GABRA1):​c.789G>A​(p.Met263Ile) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M263T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA1 NM_001127644.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.88
• Publications: 7 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001127644.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-161890982-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2136351.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 5-161890983-G-A is Pathogenic according to our data. Variant chr5-161890983-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402327.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.789G>A	p.Met263Ile	missense_variant	Exon 8 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.789G>A	p.Met263Ile	missense_variant	Exon 8 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 19 Pathogenic:1

Feb 02, 2017

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.789G>A (p.Met263Ile) in the GABRA1 gene is a de novo missense variant. A pathogenic variant at the same amino acid position (Met263) has been reported in the literature (PMID: 26918889) This variant was not found in the 1000 Genomes, Exome Variant Server (EVS), and Exome Aggregation Consortium (ExAC) databases. Thus, it is presumed to be rare. The genomic position is highly conserved and in silico algorithms predict the variant to be damaging. Based on the combined evidence, the (p.Met263Ile) variant is classified as a likely pathogenic variant for Epileptic encephalopathy, early infantile, 19. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;D;D;D;D;.;D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;.;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;.;M;.;M
PhyloP100		9.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.7	.;D;D;D;D;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	.;D;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0070	.;D;D;D;D;.;.;.;D;.
Polyphen		0.99	D;D;D;D;D;D;.;D;.;D
Vest4		0.92, 0.91, 0.92, 0.91
MutPred		0.65		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.97
MPC		2.2
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060499553; hg19: chr5-161317989;