rs786204440
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_000016.6(ACADM):c.850-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,452 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_000016.6 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.850-2A>G | splice_acceptor_variant | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.850-2A>G | splice_acceptor_variant | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000816 AC: 2AN: 245078Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132300
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1454452Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 723278
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change affects an acceptor splice site in intron 9 of the ACADM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). This variant is present in population databases (rs761317029, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with MCAD deficiency (PMID: 15832312). ClinVar contains an entry for this variant (Variation ID: 188748). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at