16-8776496-A-G
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_020686.6(ABAT):c.1269+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000941 in 1,604,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000093 ( 0 hom. )
Consequence
ABAT
NM_020686.6 splice_donor_region, intron
NM_020686.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.000007345
2
Clinical Significance
Conservation
PhyloP100: -1.24
Genes affected
ABAT (HGNC:23): (4-aminobutyrate aminotransferase) 4-aminobutyrate aminotransferase (ABAT) is responsible for catabolism of gamma-aminobutyric acid (GABA), an important, mostly inhibitory neurotransmitter in the central nervous system, into succinic semialdehyde. The active enzyme is a homodimer of 50-kD subunits complexed to pyridoxal-5-phosphate. The protein sequence is over 95% similar to the pig protein. GABA is estimated to be present in nearly one-third of human synapses. ABAT in liver and brain is controlled by 2 codominant alleles with a frequency in a Caucasian population of 0.56 and 0.44. The ABAT deficiency phenotype includes psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures, and EEG abnormalities. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 16-8776496-A-G is Benign according to our data. Variant chr16-8776496-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578433.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000106 (16/151604) while in subpopulation NFE AF= 0.000236 (16/67840). AF 95% confidence interval is 0.000147. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABAT | NM_020686.6 | c.1269+6A>G | splice_donor_region_variant, intron_variant | ENST00000268251.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABAT | ENST00000268251.13 | c.1269+6A>G | splice_donor_region_variant, intron_variant | 1 | NM_020686.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000106 AC: 16AN: 151604Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000476 AC: 11AN: 230968Hom.: 0 AF XY: 0.0000557 AC XY: 7AN XY: 125766
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GnomAD4 exome AF: 0.0000929 AC: 135AN: 1452682Hom.: 0 Cov.: 32 AF XY: 0.0000886 AC XY: 64AN XY: 721982
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GnomAD4 genome AF: 0.000106 AC: 16AN: 151604Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4AN XY: 74032
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Gamma-aminobutyric acid transaminase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change falls in intron 14 of the ABAT gene. It does not directly change the encoded amino acid sequence of the ABAT protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs372790444, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ABAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 578433). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
ABAT-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 19, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at