chr4-46965205-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000809.4(GABRA4):c.899C>A(p.Thr300Asn) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T300I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000809.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRA4 | NM_000809.4 | c.899C>A | p.Thr300Asn | missense_variant | 8/9 | ENST00000264318.4 | |
GABRA4 | NM_001204266.2 | c.842C>A | p.Thr281Asn | missense_variant | 8/9 | ||
GABRA4 | NM_001204267.2 | c.689C>A | p.Thr230Asn | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRA4 | ENST00000264318.4 | c.899C>A | p.Thr300Asn | missense_variant | 8/9 | 1 | NM_000809.4 | P1 | |
GABRA4 | ENST00000508560.5 | c.*720C>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/9 | 3 | ||||
GABRA4 | ENST00000511523.5 | c.*567C>A | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
GABRA4-related developmental and epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 31, 2022 | The GABRA4 c.899C>A (p.Thr300Asn) missense variant results in the substitution of threonine at amino acid position 300 with asparagine. To our knowledge, this variant has not been reported in the peer-reviewed literature. However, a different amino acid change at this codon, p.Thr300Ile, has been reported occurring in a de novo mosaic state in a proband with early-onset focal epilepsy and neurodevelopmental abnormalities and was shown to result in faster channel desensitization and a lack of seizure-protective neurosteroid function (Vogel et al. 2022). The c.899C>A variant is located in the second of four transmembrane domains in the conserved TTI/L motif in which de novo variants for epilepsy in other GABA receptor subunit genes have been reported (Hernandez and Macdonald 2019). The c.899C>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.899C>A (p.Thr300Asn) variant is classified as a variant of uncertain significance for GABRA4-related developmental and epileptic encephalopathy. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.