chr4-46977528-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000809.4(GABRA4):c.376A>C(p.Lys126Gln) 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
GABRA4
NM_000809.4 missense
NM_000809.4 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
GABRA4 (HGNC:4078): (gamma-aminobutyric acid type A receptor subunit alpha4) Gamma-aminobutyric acid (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. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.807
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRA4 | NM_000809.4 | c.376A>C | p.Lys126Gln | missense_variant | 4/9 | ENST00000264318.4 | |
GABRA4 | NM_001204266.2 | c.319A>C | p.Lys107Gln | missense_variant | 4/9 | ||
GABRA4 | NM_001204267.2 | c.319A>C | p.Lys107Gln | missense_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRA4 | ENST00000264318.4 | c.376A>C | p.Lys126Gln | missense_variant | 4/9 | 1 | NM_000809.4 | P1 | |
GABRA4 | ENST00000502874.1 | c.*146A>C | 3_prime_UTR_variant, NMD_transcript_variant | 3/6 | 5 | ||||
GABRA4 | ENST00000508560.5 | c.*197A>C | 3_prime_UTR_variant, NMD_transcript_variant | 4/9 | 3 | ||||
GABRA4 | ENST00000511523.5 | c.*197A>C | 3_prime_UTR_variant, NMD_transcript_variant | 4/8 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2023 | The c.376A>C (p.K126Q) alteration is located in exon 4 (coding exon 4) of the GABRA4 gene. This alteration results from a A to C substitution at nucleotide position 376, causing the lysine (K) at amino acid position 126 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of methylation at K126 (P = 0.0043);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.