rs727503796
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000019.4(ACAT1):c.826+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,607,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000019.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAT1 | NM_000019.4 | c.826+1G>T | splice_donor_variant | ENST00000265838.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAT1 | ENST00000265838.9 | c.826+1G>T | splice_donor_variant | 1 | NM_000019.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250202Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135356
GnomAD4 exome AF: 0.0000117 AC: 17AN: 1455674Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 724612
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Deficiency of acetyl-CoA acetyltransferase Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1992 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 1346617). ClinVar contains an entry for this variant (Variation ID: 166650). This variant is also known as IVS8+1g>t. Disruption of this splice site has been observed in individual(s) with beta-ketothiolase deficiency (PMID: 1346617, 15128923; Invitae). This variant is present in population databases (rs727503796, gnomAD 0.002%). This sequence change affects a donor splice site in intron 8 of the ACAT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 13, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2018 | Variant summary: ACAT1 c.826+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions are supported by several publications that report experimental evidence showing exon 8 skipping (Fukao_1992) and absent enzyme activity and protein expression (Zhang_2004). The variant allele was found at a frequency of 8.2e-06 in 245060 control chromosomes (gnomAD). The variant, c.826+1G>T, has been reported in the literature in individuals affected with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency as both a homozygous and compound heterozygous allele (Fukao_1992, Grunert_2017, Zhang_2004). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Gifu University | May 05, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at