rs615942

Variant names:

• chr17-42562786-C-A
• rs615942
• NM_025233.7:c.164C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-42562786-C-A
• chr17-42562786-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025233.7(COASY):​c.164C>A​(p.Ser55Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.547 in 1,609,410 control chromosomes in the GnomAD database, including 243,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19459 hom., cov: 32)
  • Exomes 𝑓: 0.55 (223933 hom.)
• Consequence: COASY NM_025233.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.22
• Publications: 56 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.2346416E-5).
• BP6: Variant 17-42562786-C-A is Benign according to our data. Variant chr17-42562786-C-A is described in ClinVar as Benign. ClinVar VariationId is 379956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COASY	NM_025233.7	MANE Select	c.164C>A	p.Ser55Tyr	missense	Exon 1 of 9	NP_079509.5
	COASY	NM_001042532.4		c.251C>A	p.Ser84Tyr	missense	Exon 3 of 11	NP_001035997.2	Q13057-2
	COASY	NM_001042529.3		c.164C>A	p.Ser55Tyr	missense	Exon 2 of 10	NP_001035994.1	Q13057-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COASY	ENST00000393818.3	TSL:1 MANE Select	c.164C>A	p.Ser55Tyr	missense	Exon 1 of 9	ENSP00000377406.1	Q13057-1
	COASY	ENST00000590958.5	TSL:1	c.251C>A	p.Ser84Tyr	missense	Exon 3 of 11	ENSP00000464814.1	Q13057-2
	COASY	ENST00000421097.6	TSL:1	c.164C>A	p.Ser55Tyr	missense	Exon 2 of 10	ENSP00000393564.2	Q13057-1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76366 AN: 151876 Hom.: 19437 Cov.: 32

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.476

GnomAD2 exomes AF: 0.532 AC: 132584 AN: 249248 AF XY: 0.538

Gnomad AFR exome AF: 0.427

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: 0.501

GnomAD4 exome AF: 0.552 AC: 804458 AN: 1457416 Hom.: 223933 Cov.: 69 AF XY: 0.554 AC XY: 401155 AN XY: 724372

African (AFR) AF: 0.426 AC: 14231 AN: 33414

American (AMR) AF: 0.522 AC: 23290 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10214 AN: 26082

East Asian (EAS) AF: 0.453 AC: 17929 AN: 39596

South Asian (SAS) AF: 0.632 AC: 54460 AN: 86140

European-Finnish (FIN) AF: 0.540 AC: 28189 AN: 52180

Middle Eastern (MID) AF: 0.409 AC: 2356 AN: 5760

European-Non Finnish (NFE) AF: 0.561 AC: 622068 AN: 1109454

Other (OTH) AF: 0.527 AC: 31721 AN: 60162

GnomAD4 genome AF: 0.503 AC: 76421 AN: 151994 Hom.: 19459 Cov.: 32 AF XY: 0.501 AC XY: 37210 AN XY: 74276

African (AFR) AF: 0.435 AC: 18025 AN: 41444

American (AMR) AF: 0.475 AC: 7264 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1355 AN: 3468

East Asian (EAS) AF: 0.437 AC: 2256 AN: 5166

South Asian (SAS) AF: 0.639 AC: 3078 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5617 AN: 10576

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37273 AN: 67924

Other (OTH) AF: 0.480 AC: 1012 AN: 2108

Alfa AF: 0.528 Hom.: 67439

Bravo AF: 0.491

TwinsUK AF: 0.564 AC: 2093

ALSPAC AF: 0.567 AC: 2186

ESP6500AA AF: 0.431 AC: 1897

ESP6500EA AF: 0.543 AC: 4667

ExAC AF: 0.536 AC: 65057

Asia WGS AF: 0.572 AC: 1992 AN: 3478

EpiCase AF: 0.523

EpiControl AF: 0.518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Neurodegeneration with brain iron accumulation 6 (2)
-	-	1	not provided (1)
-	-	1	Pontocerebellar hypoplasia, type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000032	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.064
Sift	Benign	0.089	T
Sift4G	Uncertain	0.034	D
Polyphen		0.80	P
Vest4		0.18
MPC		0.78
ClinPred		0.021	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.27
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs615942; hg19: chr17-40714804; COSMIC: COSV55899007; COSMIC: COSV55899007;