dbSNP rs598126: COASY:p.Thr324Thr (chr17-42564502-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_025233.7(COASY):c.972A>G(p.Thr324Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,613,628 control chromosomes in the GnomAD database, including 243,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19201 hom., cov: 31)

Exomes 𝑓: 0.55 ( 224134 hom. )

Consequence

COASY
NM_025233.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.04

Publications

48 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 17-42564502-A-G is Benign according to our data. Variant chr17-42564502-A-G is described in ClinVar as Benign. ClinVar VariationId is 379957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.62 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	HGVSp	Effect	Exon Rank	Protein	UniProt
COASY	NM_025233.7	MANE Select	c.972A>G	p.Thr324Thr	synonymous	Exon 3 of 9	NP_079509.5
COASY	NM_001042532.4		c.1059A>G	p.Thr353Thr	synonymous	Exon 5 of 11	NP_001035997.2	Q13057-2
COASY	NM_001042529.3		c.972A>G	p.Thr324Thr	synonymous	Exon 4 of 10	NP_001035994.1	Q13057-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COASY	ENST00000393818.3	TSL:1 MANE Select	c.972A>G	p.Thr324Thr	synonymous	Exon 3 of 9	ENSP00000377406.1	Q13057-1
COASY	ENST00000590958.5	TSL:1	c.1059A>G	p.Thr353Thr	synonymous	Exon 5 of 11	ENSP00000464814.1	Q13057-2
COASY	ENST00000421097.6	TSL:1	c.972A>G	p.Thr324Thr	synonymous	Exon 4 of 10	ENSP00000393564.2	Q13057-1

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

75761

AN:

151796

Hom.:

19179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.640

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.548

Gnomad OTH

AF:

0.474

GnomAD2 exomes

AF:

0.531

AC:

133422

AN:

251292

AF XY:

0.537

show subpopulations

Gnomad AFR exome

AF:

0.416

Gnomad AMR exome

AF:

0.523

Gnomad ASJ exome

AF:

0.394

Gnomad EAS exome

AF:

0.440

Gnomad FIN exome

AF:

0.533

Gnomad NFE exome

AF:

0.550

Gnomad OTH exome

AF:

0.499

GnomAD4 exome

AF:

0.551

AC:

805950

AN:

1461714

Hom.:

224134

Cov.:

AF XY:

0.553

AC XY:

402246

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.415

AC:

13881

AN:

33476

American (AMR)

AF:

0.522

AC:

23319

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

10229

AN:

26128

East Asian (EAS)

AF:

0.453

AC:

17967

AN:

39668

South Asian (SAS)

AF:

0.632

AC:

54531

AN:

86252

European-Finnish (FIN)

AF:

0.540

AC:

28821

AN:

53368

Middle Eastern (MID)

AF:

0.409

AC:

2358

AN:

5768

European-Non Finnish (NFE)

AF:

0.560

AC:

623082

AN:

1111950

Other (OTH)

AF:

0.526

AC:

31762

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

21002

42004

63006

84008

105010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17442

34884

52326

69768

87210

<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:

0.499

AC:

75814

AN:

151914

Hom.:

19201

Cov.:

AF XY:

0.498

AC XY:

36934

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.422

AC:

17493

AN:

41416

American (AMR)

AF:

0.475

AC:

7259

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1354

AN:

3470

East Asian (EAS)

AF:

0.438

AC:

2257

AN:

5154

South Asian (SAS)

AF:

0.639

AC:

3073

AN:

4810

European-Finnish (FIN)

AF:

0.530

AC:

5594

AN:

10560

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.548

AC:

37235

AN:

67912

Other (OTH)

AF:

0.478

AC:

1008

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1915

3830

5746

7661

9576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<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:

0.524

Hom.:

83985

Bravo

AF:

0.488

Asia WGS

AF:

0.572

AC:

1990

AN:

3478

EpiCase

AF:

0.523

EpiControl

AF:

0.517

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Neurodegeneration with brain iron accumulation 6 (2)

not provided (1)

Pontocerebellar hypoplasia, type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.3

(source)

DANN

Benign

0.46

PhyloP100

-1.0

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

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