rs74886553

chr17-42565654-C-Gchr17-42565654-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025233.7(COASY):c.1486-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,614,024 control chromosomes in the GnomAD database, including 2,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (191 hom., cov: 33)
  • Exomes 𝑓: 0.057 (2684 hom.)
• Consequence: COASY NM_025233.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.008581
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.44

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-42565654-C-G is Benign according to our data. Variant chr17-42565654-C-G is described in ClinVar as [Benign]. Clinvar id is 380441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42565654-C-G is described in Lovd as [Likely_benign]. Variant chr17-42565654-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COASY	NM_025233.7	c.1486-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000393818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COASY	ENST00000393818.3	c.1486-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_025233.7	P1

Frequencies

GnomAD3 genomes AF: 0.0433 AC: 6593 AN: 152212 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0478 AC: 12018 AN: 251174 Hom.: 382 AF XY: 0.0498 AC XY: 6759 AN XY: 135766

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0325

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0619

GnomAD4 exome AF: 0.0567 AC: 82902 AN: 1461694 Hom.: 2684 Cov.: 33 AF XY: 0.0567 AC XY: 41241 AN XY: 727140

Gnomad4 AFR exome AF: 0.00986

Gnomad4 AMR exome AF: 0.0325

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0546

GnomAD4 genome AF: 0.0432 AC: 6587 AN: 152330 Hom.: 191 Cov.: 33 AF XY: 0.0421 AC XY: 3134 AN XY: 74492

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.0461

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0382

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0522 Hom.: 86

Bravo AF: 0.0426

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0668

EpiControl AF: 0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Neurodegeneration with brain iron accumulation 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

COASY-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.4
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74886553; hg19: chr17-40717672;