17-42565654-C-G

Position:

chr17-42565654-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 2/3 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:6

Conservation

PhyloP100: -1.44

Variant links:

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]

COASY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
COASY	NM_025233.7 linkuse as main transcript	c.1486-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000393818.3	NP_079509.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COASY	ENST00000393818.3 linkuse as main transcript	c.1486-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_025233.7	ENSP00000377406	P1	Q13057-1

Frequencies

GnomAD3 genomes

AF:

0.0433

AC:

6593

AN:

152212

Hom.:

192

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0567

AC XY:

41241

AN XY:

727140

show subpopulations

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.:

AF XY:

0.0421

AC XY:

3134

AN XY:

74492

show subpopulations

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.:

Bravo

AF:

0.0426

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0668

EpiControl

AF:

0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neurodegeneration with brain iron accumulation 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

COASY-related disorder

Benign:1

Benign, no assertion criteria provided

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over