chr4-46974235-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000809.4(GABRA4):c.718A>T(p.Thr240Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
GABRA4
NM_000809.4 missense
NM_000809.4 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 8.02
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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRA4 | NM_000809.4 | c.718A>T | p.Thr240Ser | missense_variant | 6/9 | ENST00000264318.4 | |
GABRA4 | NM_001204266.2 | c.661A>T | p.Thr221Ser | missense_variant | 6/9 | ||
GABRA4 | NM_001204267.2 | c.661A>T | p.Thr221Ser | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRA4 | ENST00000264318.4 | c.718A>T | p.Thr240Ser | missense_variant | 6/9 | 1 | NM_000809.4 | P1 | |
GABRA4 | ENST00000502874.1 | c.*488A>T | 3_prime_UTR_variant, NMD_transcript_variant | 5/6 | 5 | ||||
GABRA4 | ENST00000508560.5 | c.*539A>T | 3_prime_UTR_variant, NMD_transcript_variant | 6/9 | 3 | ||||
GABRA4 | ENST00000511523.5 | c.*539A>T | 3_prime_UTR_variant, NMD_transcript_variant | 6/8 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151932Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249592Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134880
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GnomAD4 exome AF: 0.00000823 AC: 12AN: 1458610Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6AN XY: 725560
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151932Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74180
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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 | Sep 17, 2021 | The c.718A>T (p.T240S) alteration is located in exon 6 (coding exon 6) of the GABRA4 gene. This alteration results from a A to T substitution at nucleotide position 718, causing the threonine (T) at amino acid position 240 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0275);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at