NM_000016.6:c.469-9A>G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000016.6(ACADM):c.469-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,588,988 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000016.6 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.469-9A>G | intron_variant | Intron 6 of 11 | ENST00000370841.9 | NP_000007.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00202 AC: 308AN: 152236Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.000585 AC: 138AN: 235704Hom.: 1 AF XY: 0.000456 AC XY: 58AN XY: 127326
GnomAD4 exome AF: 0.000237 AC: 341AN: 1436634Hom.: 3 Cov.: 29 AF XY: 0.000213 AC XY: 152AN XY: 713696
GnomAD4 genome AF: 0.00204 AC: 311AN: 152354Hom.: 2 Cov.: 33 AF XY: 0.00189 AC XY: 141AN XY: 74512
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Uncertain:1Benign:3
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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not specified Benign:2
Variant summary: ACADM c.469-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00074 in 262480 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0074 in the gnomAD database. The observed variant frequency within African control individuals is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0054), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.469-9A>G in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -
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not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at