1-75761371-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_000016.6(ACADM):c.1194+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,626 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 Pathogenic (★★).
Frequency
Consequence
NM_000016.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1194+1G>A | splice_donor_variant | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1194+1G>A | splice_donor_variant | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249654Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135078
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461452Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727030
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 21, 2018 | Variant summary: ACADM c.1194+1G>A 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: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Andresen_2012 and Bruun_2013). The variant allele was found at a frequency of 8.2e-06 in 244600 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (8.2e-06 vs 0.0054), allowing no conclusion about variant significance. c.1194+1G>A has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency. These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADM protein in which other variant(s) (p.Leu409Hisfs*5) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 11, but is expected to preserve the integrity of the reading-frame (PMID: 22542437, 23810226). ClinVar contains an entry for this variant (Variation ID: 555602). Disruption of this splice site has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 22542437). This variant is present in population databases (rs769331400, gnomAD 0.006%). This sequence change affects a donor splice site in intron 11 of the ACADM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 02, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at