chr17-42562674-C-CT
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_025233.7(COASY):c.53dup(p.Ala19SerfsTer45) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000202 in 1,537,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
COASY
NM_025233.7 frameshift
NM_025233.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.55
Genes affected
COASY (HGNC:29932): (Coenzyme A synthase) Coenzyme A (CoA) functions as a carrier of acetyl and acyl groups in cells and thus plays an important role in numerous synthetic and degradative metabolic pathways in all organisms. In eukaryotes, CoA and its derivatives are also involved in membrane trafficking and signal transduction. This gene encodes the bifunctional protein coenzyme A synthase (CoAsy) which carries out the last two steps in the biosynthesis of CoA from pantothenic acid (vitamin B5). The phosphopantetheine adenylyltransferase domain of this bifunctional protein catalyzes the conversion of 4'-phosphopantetheine into dephospho-coenzyme A (dpCoA) while its dephospho-CoA kinase domain completes the final step by phosphorylating dpCoA to form CoA. Mutations in this gene are associated with neurodegeneration with brain iron accumulation (NBIA). Alternative splicing results in multiple isoforms. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.969 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-42562674-C-CT is Pathogenic according to our data. Variant chr17-42562674-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2079887.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COASY | NM_025233.7 | c.53dup | p.Ala19SerfsTer45 | frameshift_variant | 1/9 | ENST00000393818.3 | NP_079509.5 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COASY | ENST00000393818.3 | c.53dup | p.Ala19SerfsTer45 | frameshift_variant | 1/9 | 1 | NM_025233.7 | ENSP00000377406 | P1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000204 AC: 4AN: 196138Hom.: 0 AF XY: 0.0000190 AC XY: 2AN XY: 105362
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GnomAD4 exome AF: 0.0000195 AC: 27AN: 1384778Hom.: 0 Cov.: 30 AF XY: 0.0000205 AC XY: 14AN XY: 681636
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GnomAD4 genome 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74372
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurodegeneration with brain iron accumulation 6 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 03, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with COASY-related conditions. This variant is present in population databases (rs751753677, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ala19Serfs*45) in the COASY gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COASY are known to be pathogenic (PMID: 24360804, 30089828). - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2022 | Does not currently meet published gene-disease clinical validity criteria for this gene (Smith, 2017) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at