NM_025233.7:c.1486-5C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025233.7(COASY):c.1486-5C>G variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.008581

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.44

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
pontocerebellar hypoplasia, type 12
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

COASY links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 380441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025233.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COASY	NM_025233.7	MANE Select	c.1486-5C>G	splice_region intron	N/A	NP_079509.5
COASY	NM_001042532.4		c.1573-5C>G	splice_region intron	N/A	NP_001035997.2	Q13057-2
COASY	NM_001042529.3		c.1486-5C>G	splice_region intron	N/A	NP_001035994.1	Q13057-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COASY	ENST00000393818.3	TSL:1 MANE Select	c.1486-5C>G	splice_region intron	N/A	ENSP00000377406.1	Q13057-1
COASY	ENST00000590958.5	TSL:1	c.1573-5C>G	splice_region intron	N/A	ENSP00000464814.1	Q13057-2
COASY	ENST00000421097.6	TSL:1	c.1486-5C>G	splice_region intron	N/A	ENSP00000393564.2	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

GnomAD2 exomes

AF:

0.0478

AC:

12018

AN:

251174

AF XY:

0.0498

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 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

African (AFR)

AF:

0.00986

AC:

330

AN:

33480

American (AMR)

AF:

0.0325

AC:

1453

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

2873

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39688

South Asian (SAS)

AF:

0.0337

AC:

2907

AN:

86258

European-Finnish (FIN)

AF:

0.0387

AC:

2063

AN:

53366

Middle Eastern (MID)

AF:

0.0562

AC:

324

AN:

5768

European-Non Finnish (NFE)

AF:

0.0626

AC:

69650

AN:

1111888

Other (OTH)

AF:

0.0546

AC:

3296

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

4462

8925

13387

17850

22312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2504

5008

7512

10016

12520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0432

AC:

6587

AN:

152330

Hom.:

191

Cov.:

AF XY:

0.0421

AC XY:

3134

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0107

AC:

443

AN:

41582

American (AMR)

AF:

0.0461

AC:

705

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

371

AN:

3468

East Asian (EAS)

AF:

0.000964

AC:

AN:

5186

South Asian (SAS)

AF:

0.0323

AC:

156

AN:

4828

European-Finnish (FIN)

AF:

0.0382

AC:

405

AN:

10610

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0632

AC:

4298

AN:

68034

Other (OTH)

AF:

0.0502

AC:

106

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

323

646

970

1293

1616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

COASY-related disorder (1)

Neurodegeneration with brain iron accumulation 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.4

(source)

DANN

Benign

0.58

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over